Editorial

This special supplement of the Revista de Psiquiatria Clínica (RPC) contains the abstracts of all papers presented during the 1st Schizophrenia International Research Society (SIRS) South America Meeting, held in São Paulo from August 5th to 7th, 2011.
Organizing the first Regional Meeting for the SIRS required large amounts of expertise and effort. We want to acknowledge the significant contributions of the Local and South American Organizing Committees, as well as the official support of the Associação Brasileira de Psiquiatria (ABP) and the Associação Brasileira de Neurociência Clínica (ABraNeC).
In addition to the contributions of international experts from SIRS, a large number of South American scientists have brought their most recent findings to be presented at the conference. This shows the remarkable growth of psychiatric research in our continent in the past few years, helping to increase knowledge about the causes, pathophysiology and treatment of schizophrenia.
We believe that all attendees will profit from taking part in what promises to be a state-of-the-art scientific meeting, and greatly enjoy the contents of this supplement.

The Local Organizing Committee

Geraldo Busatto, Ph.D.
Associate Professor, Department of Psychiatry
Faculdade de Medicina
Universidade de São Paulo

Wagner Gattaz, M.D., Ph.D.
Professor and Chairman, Department of Psychiatry
Faculdade de Medicina
Universidade de São Paulo

 

Molecular genetic analyses of schizophrenia in South America


Aida Ruiz1, Robin Murray2, John Powell2, Eduardo Miranda1, Pak Sham3

1Universidad de Chile, Santiago, Chile/2King’s College London, London, United Kingdom/3King’s College London, London, United Kingdom

Background: In the past decades, tremendous efforts have been invested in finding genetic causes of schizophrenia. Earlier schizophrenia genetic studies were mainly focused on genome-wide linkage studies (GWLS), and candidate region or candidate gene association studies. More recent studies have used modern high-throughput genomic technologies on large patient samples, for example genome-wide association studies (GWAS), copy number variations (CNV) and large-scale candidate gene re-sequencing studies. These studies have been mainly carried out in populations of European origin. The main objective of this study was to review molecular genetic analyses of schizophrenia in South American samples, which are the result of admixture between people of European, Native American or African ancestries. Methods: A search for molecular genetic studies of schizophrenia in South American samples was carried out using Medline. Articles published during the last decade, and available reports presented in conferences were included. Study design, sample size, statistical power calculation, molecular analysis of population structure, and analysis of intermediate phenotypes (cognitive, neurophysiological, and imaging) were the main aspects evaluated. Descriptive statistical analysis was performed using SPSS statistical software. Results: Reports on molecular genetic association studies of potential candidate genes in samples from Brazil, Chile, and Colombia were found, using both case-control and family designs. Most candidate genes studied in these populations did not show significant association with schizophrenia, with the exception of the Capon gene in a Colombian sample, and Notch, iPLA2 and NRGN genes in Brazilian analyses. None of the reports analysed association with intermediate phenotypes. Regarding statistical analysis, most studies did not perform statistical power calculation, and did not considered molecular analysis of population stratification. Studies using more recent approaches, such as GWAS, CNV, and large-scale candidate gene resequencing, were not found in this review.
Discussion: Some associations with candidate genes were described in some South American populations. These results could be biased due to some methodological limitations, such as insufficient sample size to detect small effect size genes and the lack of population stratification control. It has been described that in admixed South American populations, the relative contributions of the three ancestral continental groups can vary substantially between sub-groups (e.g. between Brazilians and Chileans) and also among individuals within the same sub-group. This heterogeneity is a problem both for evolutionary studies and for genetic association studies in South American populations, unless genetic ancestry can be measured. Low levels of genetic diversity and high levels of linkage disequilibrium in the Native American derived DNA sequences have been observed, consistent with a recent, severe population bottleneck associated with the initial peopling of the Americas. Admixed South American populations could present a different pattern of linkage disequilibrium from other populations, offering advantages in the fine mapping of risk loci for complex disorders, using the most recent molecular sequencing technologies.



Functional polymorphisms of DGCR2 gene may play on schizophrenia pathogenesis and on antipsychotics treatment response


Sintia I. Belangero1,2, Ary Gadelha2,3, Vanessa K. Ota1,2, Denise M. Christofolini1, Fernanda T. Bellucco1, Marcos L. Santoro1,2, Airton F. Santos Filho2,3, Vinicius C. Mrad1,2, Leticia M. Spindola1,2, Deyvis M. Rocha2,3, Rodrigo A. Bressan2,3, Maria I. Melaragno1, Marilia A. Smith1, Jair J. Mari3

1Divisão de Genética, Departamento de Morfologia e Genética, Universidade Federal de São Paulo, São Paulo, SP, Brasil/2Laboratório Interdisciplinar de Neurociências Clínicas, Departamento de Psiquiatria, Universidade Federal de São Paulo, São Paulo, SP, Brasil/3Departamento de Psiquiatria, Universidade Federal de São Paulo, São Paulo, SP, Brasil


Background
: Several studies have shown that 22q11 deletion is an important risk factor for schizophrenia. DGCR2 gene, located at 22q11.2, encodes an adhesion receptor protein. The genetic and functional evidence suggests an association of the DGCR2 gene and schizophrenia, although its role in the pathology still is not clear. A study has showed that its expression is elevated in dorsolateral prefrontal cortex in patients with schizophrenia and also elevated in rats under treatment with antipsychotic drugs when compared with non-treated rats. We aimed to investigate the interaction between three functional polymorphisms of DGCR2 gene and its influence on treatment response and on schizophrenia presence. Methods: We studied 188 schizophrenia patients from the Schizophrenia Program (PROESQ) and 199 healthy controls recruited from the Interdisciplinary Laboratory of Clinical Neurosciences (LiNC), both at Universidade Federal de São Paulo (Unifesp). Patients were genotyped for rs2073776 (T/C), rs807759 (A/G) and rs2072123 (A/G) DGCR2 gene polymorphisms using TaqMan? probe-based real-time PCR assay. We verified if DGCR2 polymorphisms were in Hardy-Weinberg equilibrium using chi-square test. Interaction between DGCR2 polymorphisms was verified using logistic regression analysis. Results: We found a putative interaction effect between two of these DGCR2 polymorphisms (rs2073776 and rs2072123) upon schizophrenia (p = 0.042). Carriers of AG/TG genotypes combination (rs2073776 and rs2072123 polymorphisms, respectively) present a chance near nine times higher of being in the schizophrenia group than GG/CC carriers (OR = 8.9). Regarding treatment response, our data show an association between rs807759 polymorphism and refractoriness (p = 0.035), which AA carriers presented a risk five times lower in refractoriness than GG carriers (OR = 0.2), playing as a protector factor against treatment refractoriness. Discussion: Our findings revealed that DGCR2, a gene located in a known risk region for schizophrenia, might be involved not only in the schizophrenia pathogenesis as well might play a role in the therapeutic effects of antipsychotic drugs. Financial support: FAPESP and CNPq.

Association between NOS1AP gene and clinical subtypes of schizophrenia

 
Jenny Garcia-Valencia
1, Ana V. Valencia-Duarte1, Ana L. Paez-Vila1, Barbara Kremeyer2, Carlos A. Palacio-Acosta1, Jorge Ospina-Duque1, Angela Rodríguez-Betancur1, Manuela Gaviria-Ospina1, Gabriel Bedoya-Berrio1, Maria P. Arbelaez-Montoya1, Andres Ruiz-Linares2

1Universidad de Antioquia, Medellín, Antioquia, Columbia/2University College of London, London, London, United Kingdom


Background: Recent studies have implicated a region on chromosome 1q23, including the NOS1AP gene, in susceptibility to schizophrenia. However, replication studies have been inconsistent, a fact that could partly relate to the marked psychopathological heterogeneity of schizophrenia. The aim of this study is 1) to empirically identify subtypes of schizophrenia based on symptoms recorded during the duration of the disorder, and 2) to determine the association among each subtype and polymorphisms in the NOS1AP gen. Methods: Clinical subtypes of schizophrenia were identified using Multiple Correspondence Analysis and Hierarchical Classification. We compared genetic variants in the NOS1AP gene between each subtype and a control group. We adjusted by age, sex and ancestry by means of ancestry informative markers.
Results: We identified five clinical subtypes: 1) Paranoid without influence experiences, 2) disorganized, 3) catatonic, 4) disorganized with hallucinations and delusions, and 3) paranoid with influence experiences. There was an association of the disorganized subtype with the C/T genotype (OR = 2.35, 95CI%: 1.11- 4.98) and the presence of allele C (OR = 2.30, 95CI%: 1.08 – 4.91) of rs945713 marker. We did not find association between NOS1AP markers and the other subtypes. Discussion: We found a significant associative of a marker in the NOS1AP gene with the “disorganized subtype”. This result suggests that NOS1AP influence in the vulnerability to a specific subtype of schizophrenia. The subtyping strategy might facilitate the molecular genetics research in psychiatric disorders. 

Greater prevalence of ultra-rapid drug metabolizers between refractory schizophrenia patients? A pharmacogenetic study

Martinus T. van de Bilt1, Carolina M. Prado1, Alexandre A. Loch1, Rafael A. T. Sousa1, Marcus V. Zanetti1, Wagner F. Gattaz1

1Laboratório de Neurociências (LIM-27), Instituto de Psiquiatria, Universidade de São Paulo, São Paulo, SP, Brasil


Background
: The family of the CYP450 enzymes has been the mainstream of studies in pharmacogenetics. All genes that encode these enzymes are highly polymorphic leading to different metabolic activities. Most of the available data about the influence of the genetic polymorphisms of the CYP2D6 and CYP2C19 refer to antidepressants, for which dose adjustments have been suggested based on genotype. However, there are no concrete evidences validating genotype based antipsychotics adjustments. We investigate the hypothesis that the prevalence of ultra rapid metabolizers of neuroleptics is increased among refractory schizophrenia patients. Methods: The study enrolled patients who were referred to treatment with clozapine because they were refractory to conventional antipsychotics (non responders); patients who responded to conventional antipsychotics (responders); and normal controls. All patients had their diagnosis reviewed using the SCID. The psychopathology was assessed by the PANSS. To obtain inter-rater reliability, the first 20 patients were rated jointly by the researchers. DNA was obtained from peripheral blood samples and extracted by the saline method. The polymorphisms were screened by allelic discrimination using the TaqManR system on real time PCR. A total of 146 individuals were genotyped for CYP2D6: 29 responders, 45 non-responders and 72 controls. For CYP219 183 individuals were genotyped: 42 responders, 43 non-responders, 98 controls. The phenotypes were classified in extensive metabolizers (EMs), poor metabolizers (PMs), intermediary metabolizers (IMs) and ultra-rapid metabolizers (UMs). Statistical analysis was carried out with the SPSS software, version 14.0. Levels of significance 0,1 > p > 0,05 were designated as tendence and P < 0,05 as statistically significant difference. The data on the predicted phenotypes were submitted to the X² Pearson Test to determine statistically significant difference in the distribution of the phenotypes between the refractory and non refractory schizophrenia patients and controls. Results: The 2 groups studied – non-responders and responders – did not differ i < a name = “_GoBack” > n any of the clinical-demographical features evaluated. The distribution of the predicted CYP2D6 and CYP2C19 phenotypes were as follows:
 
For CYP2D6:
Non-responders: 86,7% EMs, 8,9% IMs, 4,4% PMs e 0,0% UMs
Responders: 89,7% EMs, 6,9% IMs, 3,4% PMs e 0,0% UMs
Controls: 81,9% EMs, 6,9% IMs, 4,2% PMs e 6,9% Ums

For CYP2C19:
Non-responders: 34,9% EMs, 23,3% IMs,  4,7% PMs e 37,2% UMs
Responders: 47,6% EMs, 14,3% IMs, 7,1% PMs e 31,0% UMs
Controls: 45,9% EMs, 19,4% IMs, 2,0% PMs e 32,7% UMs
 
Statistical analysis showed no significant association between the distribution of the predicted CYP2C19 phenotypes and the non-responder condition (p = 0,636); and between the distribution of the predicted of CYP2D6 phenotypes and the non-responder condition (p = 0,480).

Discussion: In a clinical sample of schizophrenics, we did not find a significant difference between non-responder and responder patients in relation to the predicted phenotypes of the genes CYP2C19 and CYP2D6. Therefore, our findings do not reinforce the inclusion of genotyping of the referred genes as a tool in the clinical decision making in refractory schizophrenia.


What does proteomics in human brain tissue tell us about schizophrenia?

Daniel Martins-de-Souza
1,2,3, Wagner F. Gattaz2, Andrea Schmitt4, Giuseppina Maccarrone3, Peter Falkai4, Emmanuel Dias-Neto2, Chris W. Turck3

1University of Cambridge, Cambridge, United Kingdom/2Universidade de São Paulo, São Paulo, SP, Brasil/3Max Planck Institute of Psychiatry, Munich, Germany/4University of Goettingen, Goettingen, Germany


Background
: Schizophrenia (SCZ) biomarkers have been initially searched by genotyping techniques, genome wide association studies and large-scale transcriptome analyses. Afterwards, proteome analysis has emerged in this context as a promising strategy. The search for protein biomarkers of SCZ in human brain tissue via proteomics aimed primarily to provide information on the risk for the disease, to contribute to the early diagnosis and to the prediction of therapeutic response. After several proteomic studies conducted in several brain regions, it became clear that the secondary objectives of this type of research, which were to provide detailed information about the pathophysiology of the disease and to further confirm the importance of certain biochemical pathways, have produced more interesting findings, although potential biomarkers candidates have also been pointed out as primarily expected. Methods: We have studied the post-mortem proteomes of the dorsolateral prefrontal cortex, anterior temporal lobe, Wernicke’s area, anterior cingulate cortex and thalamus from SCZ patients comparing to healthy controls using different proteomic methodologies such as two-dimensional gel electrophoresis followed by mass spectrometry as well as shotgun proteomics. For the second approach, extracted proteins were labeled with stable isotopes for proteome quantification, digested and the resultant peptides separated by isoelectrofocusing and reverse-phase HPLC prior to MALDI-TOF/TOF mass spectrometry. Results: We have found the most often alterations in energy metabolism, oligodendrocyte-function and myelinization, calcium homeostasis and cytoskeleton. Moreover, we have revealed the differential expression of a number of hypothetical or putative proteins, which might be interesting targets to further studies considering their underlie information. Several protein biomarker candidates such as myelin basic protein and myelin oligodendrocyte protein were evaluated and validated by western blot in some of the described brain regions as well as in cerebrospinal fluid from a separate sample cohort. A number of glycolysis enzymes have been found differentially expressed in the analyzed brain regions, leading us to quantify the levels of pyruvate and NADPH in thalamus, which were indeed found altered. Discussion: The recurrent identification and validation of inter-related protein clusters, determined in different samples by different proteomic approaches not only strongly reinforces the putative involvement of certain pathways in SCZ, but also reveal new potential biomarkers and paves the way to the development of new therapeutic strategies in order to contribute for reducing the social and cognitive consequences of this disorder.

Expression of neurotransmitter receptor and regulator genes in the prefrontal cortex in a new animal model of schizophrenia: the spontaneous hypertensive rats (SHR)

Marcos L. Santoro1,2, Camila M. Santos2, Mariana C. Diana2,3, Vanessa K. Ota1,2, Vinicius C. Mrad1,2, Leticia M. N. Spindola1,2, Marilia A. C. Smith1, Vanessa C. Abilio2,3, Sintia I. Belangero1,2

1Divisão de Genética, Departamento de Morfologia e Genética, Universidade Federal de São Paulo, São Paulo, SP, Brasil/2Laboratório Interdisciplinar de Neurociências Clínicas, São Paulo, SP, Brasil/3Departamento de Farmacologia, Universidade Federal de São Paulo, São Paulo, SP, Brasil

Background
: Schizophrenia is a complex and severe mental illness that affect 0,3% to 1,6% of the general population. Genetic and environmental factors interact to develop the disease. The symptoms are characterized in positive – hallucinations and delusions, negative – reduced expression of normal behaviors (reduced social interaction), and cognitive – reduced cognitive capabilities (impaired attention). Recently, our group suggested that the SHR (Spontaneously Hypertensive Rat) strain – based on its behavioral, pharmacological and neurochemical profile – could be a useful animal model to study several aspects of schizophrenia. In this respect, the aim of the present study was to characterize gene expression profiles of neurotransmitters receptors and regulators in prefrontal cortex in SHR and Wistar rats. Methods: We have studied SHR (n = 5) and Wistar (n = 6) adult males rats (6 months). The animals were euthanized and the prefrontal cortex was dissected, then the RNA was extracted and converted to cDNA. To perform the gene expression analysis we used the PCRarray technique, which verifies the expression of 84 genes related to neurotransmission plus five housekeeping genes simultaneously. We utilized the < a href = http://sabioscience.com/pcr/arrayanalysis.php > Web-Based PCR Array Data Analysis software, which uses t-test to investigate the significance of each gene. It was considered relevant p-values less than 0.05 and fold regulation greater than 1.3. Results: 14 genes showed to be under expressed, five of them have already been associated with schizophrenia: Chat (-1.58 fold; p = 0.029), Drd1a (-1.9 fold; p = 0.024), Gabra1 (-1.34 fold; p = 0.036), Gabrb3 (-1.47 fold; p = 0.039), Gabrg2 (-1.34 fold; p = 0.035). Two of them are related to blood pressure: Brs3 (-1.56 fold; p = 0.049), Qrfpr (-6.47 fold; p = 0.005). And seven of them are involved in different neurotransmitter pathways, however, there has been no citation associating them with schizophrenia yet: Glra2 (-1.3 fold; p = 0.003), Prokr1 (-1.97 fold; p = 0.018), Prokr2 (-1.5 fold; p = 0.003), Npy1r (-1.34 fold; p = 0.034), Npy5r (-1.33 fold; p = 0.038), Slc5a7 (-1.36 fold; p = 0.034), Tacr3 (-1.64 fold; p = 0.025). Discussion: Previous studies showed that the prefrontal cortex of schizophrenia patients has a reduction of DRD1 gene expression, and that this gene seems to be related to the negative and cognitive symptoms. Likewise, GABAergic system is under expressed in patients compared to controls, and a study found association of GABRA1 and GABRG2 risk haplotypes with decreased expression. A CHAT activity study has also identified significant reductions mainly in nucleus accumbens and pontine tegmentum of patients, which is correlated significantly with measures of cognitive performance in the disorder. Those three pathways altered in the prefrontal cortex of SHR group could be the cause of their impairment of cognition and social interaction, resembling the negative and cognitive symptoms in schizophrenia. Moreover, the expression of Brs3 and Qrfpr were altered probably due to the hypertensive condition of the SHR. It is worth noting that all 14 altered genes in SHR were under expressed, suggesting a possible hypofunction of the prefrontal cortex. In conclusion, our data show that SHR presented alteration in gene expression profiles in the prefrontal cortex that have been related to schizophrenia. In this way, these data added to our previous work reinforce this strain as an animal model to study several aspects of schizophrenia. Further expression studies of our group will search for altered neurotransmission genes in other brain regions to better characterize SHR genetically. Financial support: Fapesp.  

Oral Session 2 – Boundaries of Psychotic Disorders

Graph analysis of psychotic speech: differential diagnosis between schizophrenia and mania

Natália B. Mota1,2,3, Nivaldo Vasconcelos1,2,4, Nathália M. Lemos1,2, Ana C. Pieretti2,3, Osame Kinouche5, Mauro Copelli6,7, Sidarta Ribeiro1,2,7

1Universidade Federal do Rio Grande do Norte, Natal, RN, Brasil/2Edmond e Lily Safra, Instituto Internacional de Neurociências de Natal, Natal, RN, Brasil/3Programa de Residência em Psiquiatria, Hospital Universitário Onofre Lopes, Universidade Federal do Rio Grande do Norte, Natal, RN, Brasil/4Departamento de Sistemas e Computação, Universidade Federal de Campina Grande, Campina Grande, PB, Brasil/5Departamento de Física, Universidade de São Paulo, Ribeirão Preto, SP, Brasil/6Departamento de Física, Universidade Federal de Pernambuco, Recife, PE, Brasil/7Programa de Pós-Graduação em Neurociência, Universidade Federal do Rio Grande do Norte, Natal, RN, Brasil

Background
: The differential diagnosis between manic and schizophrenic patients presents a substantial challenge during acute psychotic crises. Successful diagnosis requires long-term training in the identification of symptoms assessed by a qualitative analysis of speech. Here we sought to quantify differences in the speech graph structure of schizophrenic and manic psychotic subjects. Methods: We recorded oral interviews with 24 subjects (8 schizophrenics, 8 maniacs and 8 controls) and applied the SCID DSM IV, PANSS and BPRS scales to identify psychotic symptoms. Patients were asked to report on recent dreams. The reports were transcribed, parsed into semantics units (SU) and represented by a directed graph in which each node corresponded to a SU and each edge represented the link between consecutive SU. Twelve graph attributes were calculated (nodes, edges, self-loops, parallels edges, largest connected component, largest strongly connected component, average total degree, wake nodes, wake edges, loops with one, two and three nodes), and non-parametric statistical tests were used to assess significant differences. A naive Bayes classifier was trained with different combinations of the graph attributes as inputs. The output was a binary decision in the form “is this graph from a given group or not”. To quantitatively compare the schizophrenic, manic and control groups, we calculated the sensitivity and specificity of classification and a receiver operating characteristic (ROC) curves were built based on the output of the classifier, using the area under the ROC curve (AUC) as a metric of classification quality (AUC = 0.5 means classification at chance level and AUC = 1 means maximum classification quality). We also calculated the kappa statistic to assess the agreement between psychiatric diagnosis and group classification based on speech graphs. (Values > 0.6 mean good agreement and > 0.8 mean great agreement.)
Results: Manic reports contained more words than schizophrenic group (p = 0.0067) and almost all attributes were significantly higher. When the data were normalized by the total number of words in each report, graphs from the manic group still displayed more parallel edges (p = 0.0050) than graphs from the schizophrenic group, with more loops than control group (p = 0.0019), reflecting the “logorrhea” symptom typical of maniacs. Conversely, schizophrenic reports presented more nodes (p = 0.0114) and a higher average degree (p = 0.0074) than graphs from maniacs, reflecting “poor speech”. Manic patients had a significantly higher rate of interruptions of the dream report to comment on unrelated waking events. This effect persisted when the data were normalized by the total number of words (p = 0.0196), and seems to reflect the symptom of “flight of thoughts”. The classifier based on graph attributes sorted schizophrenic from manic group with 93% of sensitivity and specificity (kappa: 0.88, AUC: 0.88). Schizophrenics were sorted from control group with 93% of sensitivity and specificity (kappa: 0.88, AUC: 0.97) and maniacs from control group with 81% of sensitivity and specificity (kappa: 0.63, AUC: 0.94). None of these graph attributes were correlated with BPRS and PANSS total score, which indicates that our approach is not redundant with psychiatric scales, but rather measures complementary features such as structural speech symptoms. Discussion: Altogether, the analyses reveal quantitative differences between speech graphs from schizophrenic and manic psychotic patients, which may reflect classical symptoms not well grasped by standard psychiatric scales. Quantitative speech analysis can therefore help the differential diagnosis of psychosis.

The efficacy of lithium in psychotic features of bipolar mania: early improvement and its association with later response

Rafael T. de Sousa
1, Micheli Figueiró1, Marcus V. Zanetti1, Wagner F. Gattaz1, Rodrigo Machado-Vieira1

1Universidade de São Paulo, São Paulo, SP, Brasil

Background: Few studies have evaluated lithium’s efficacy in psychotic symptoms in bipolar mania. The identification of early clinical predictors for the antimanic efficacy with lithium is sparse and this information is essential for therapeutic decisions in clinical practice. The lack of knowledge on lithium early efficacy is mostly due to the widely prescribed first-generation antipsychotic agents combined with mood stabilizers in the first weeks of treatment. This study addresses the antipsychotic efficacy of lithium in acute mania and evaluates early improvement associated with lithium treatment as a predictor of later response or remission. Methods: Thirty-two patients with psychotic mania (total YMRS > 21 at baseline and YMRS-8 item, score = 8) were compared to fourteen subjects in a manic episode without psychotic symptoms. All subjects started on lithium monotherapy (flexible dose reaching therapeutic levels) and were clinically monitored during a 4-week follow-up period. Subjects with rapid cycling and mixed episodes and substance abuse were excluded. Analyses were performed to determine overall efficacy of lithium in psychotic versus non-psychotic and whether early improvement of psychotic symptoms predicted response (> 50% decrease in total YMRS scores) or remission (YMRS < 8) at endpoint. Results: Lithium showed a similar efficacy in mania with psychotic symptoms (delusions and hallucinations) versus non-psychotic mania. More than half of all patients in both groups had response after the 4-week follow-up period. Subjects with psychotic mania who improved psychotic symptoms after one week of treatment were likely to become responders at the endpoint. Discussion: To our knowledge, this is the first study showing the clinical efficacy of lithium monotherapy in psychotic features of bipolar mania. Also, subjects who had early improvement of psychotic symptoms presented improved overall antimanic response at the endpoint. Recent evidences suggest that lithium modulates glutamatergic activity in hippocampus and, thus, might also regulate dopaminergic firing rate in mesolimbic-cortical circuitry, which may explain its antipsychotic properties.

Dysfunctional family environment in offspring of parents with psychotic and non-psychotic bipolar disorder


Carolina R. L. Moreira
1, Guilherme S. Ferreira1, Edmir Nader1, Bernardo C. Gomes1, Ana Maria Teixeira1,2, Geraldo F. Busatto2, Beny Lafer1, Ana Kleinman1, Sheila C. Caetano1,2

1Programa de Pesquisa em Transtorno Bipolar, Departamento de Psiquiatria, Faculdade de Medicina da Universidade de São Paulo, São Paulo, SP, Brasil/2Laboratório de Neuroimagem em Psiquiatria (LIM-21), Departamento de Psiquiatria, Faculdade de Medicina da Universidade de São Paulo, São Paulo, SP, Brasil

Background
: Children of parents with bipolar disorder (BD) are at heightened risk for developing mood disorders and other psychiatric disorders. Environmental influences including family traits have been established as risk factors for psychopathology in children of affectively disordered parents. Using the Family Environment Scale (FES), studies have found lower cohesion and organization and higher conflict in BD families when compared to normative (United States population) FES data and healthy families (HF). Moreover, the presence of psychotic symptoms in BD parents may have an impact on family structure. Specifically lower cohesion has been associated with psychotic features in BD parents. The goal of our study was to evaluate whether psychotic symptoms in BD parents were related to dysfunctional family environment when compared to BD parents without psychosis. We also intended to study the environment of families with at least one parent with BD compared to families with parents without any DSM-IV Axis I disorder. In addition, in order to assess the influence of offspring psychopathology on family environment, we compared BD families with offspring with BD or other psychiatric diagnoses, healthy offspring, and HF. To our knowledge, this is the first study that examined family environment and psychosis in BD parents. Methods: 47 BD families met the inclusion criteria: at least one parent with a DSM-IV BD type I diagnosis – using the Structured Clinical Interview for the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition; age between 18 and 65 years old and at least one offspring. Twenty-six control families were recruited through advertisement. Exclusion criteria for the control parents were any DSM-IV Axis I Disorders. Offspring of BD parents and healthy controls aged 6 to 18 years old were ascertained through the K-SADS-PL interview. Exclusion criteria were mental retardation and organic illnesses for both groups. One parent in each family was asked to complete the FES, a 90-item, true or false questionnaire evaluating the family in different dimensions. Results: We did not find any differences in FES subscales between BD parents with and without psychotic symptoms.  Families with BD parents reported lower levels of family cohesion (p = 0.002), intellectual-cultural orientation (p = 0.02), active-recreational orientation (p = 0.001), moral-religious emphasis (p = 0.01), organization (p = 0.001) and higher levels of conflict (p = 0.003) when compared to HF. Secondary analyses revealed lower levels of family cohesion (p = 0.007) and active-recreational orientation (p = 0.003) and higher levels of conflict (p = 0.007) and control (p = 0.02) in families with offspring with BD and other psychiatric diagnoses when compared to healthy offspring and controls. Healthy offspring reported lower levels of organization (p = 0.003) compared to offspring with BD or other psychiatric diagnoses and controls. Discussion: Families with BD parents presented lower levels of cohesion and organization and higher levels of conflict compared to healthy families. These dysfunctional family features were not related to the presence of psychotic symptoms in BD parents.

Psychotic and non-psychotic unipolar depression: clinical and biological differences


Maristela S. Schaufelberger1, Helena P. Sá1, Aline G. Balestra1, Carlos E. Garrido1, Paula R. Diniz1,2, Antonio C. Santos1, Cristina M. Del Ben1

1Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, SP, Brasil/2Universidade Federal de Pernambuco, Recife, PE, Brasil

Background
: Psychotic symptoms (delusions or hallucinations) can be found in 20 percent of patients experience a depressive episode of Major Depressive Disorder (MDD). Such features are believed to be associated with higher rates of depressive symptoms, suicide risk, psychomotor abnormalities and poorer outcomes. Despite the high prevalence and specific clinical profile, the biological aspects of psychotic MDD (P-MDD) remain to be elucidated. Numerous neuroimaging studies have shown brain abnormalities associated with non-psychotic MDD (NP-MDD); however, only a minority of those has investigated psychotic patients. In order to evaluate the neurobiological aspects underlying this subtype of mood disorder, we investigated biochemical and morphometric brain differences between psychotic and non-psychotic MDD patients. Methods: Using a 3T Philips MRI scanner, we examined 21 P-MDD, 23 NP-MDD and 23 age- and gender-paired healthy subjects. All patients met DSM-IV criteria for unipolar MDD and had a current diagnosis of severe depressive episode. We acquired a 1H-spectroscopy examination with a 1 x 2 x 3 cm single-voxel placed in the anterior cingulate gyrus and a 3D-TI MPRAGE volumetric sequence. Spectroscopy data were processed with LCModel and structural images were processed with FreeSurfer (surfer.nmr.mgh.harvard.edu). Measures of absolute metabolite levels (NAA, choline compounds [PC+PC], PCr + Cr, myoinositol, glutamate and Glu + Gln), a priori defined regional cortical thickness (orbitofrontal and cingulate cortex) and volumes (medial temporal structures, basal ganglia, insula) were analyzed with Analysis of Variance, Multivariate, with SPSS; statistical significance was established at p < 0.05. Results: P-MDD and NP-MDD did not differ in terms of severity of depressive symptoms (assessed by the Hamilton scale), number of previous episodes, and age of onset of depression; however, P-MDD had a significant lower global functioning and higher frequency of current suicide attempts. P-MDD had lower levels of NAA in comparison with NP-MDD (p = 0.03) and lower levels of GPC + PC in comparison to both NP-MDD (p = 0.003) and controls (p = 0.003). Cortical thickness reduction in the psychotic patients was found in the cingulate cortex, isthmus area (in the left, when compared to NP-MDD, p = 0.014; and in the right, when compared to controls, p = 0.008) and in the left medial orbitofrontal cortex when compared to controls (p = 0.029). These areas also show a significant inverse correlation with thought disturbances assessed with BPRS (p = 0.01, for the right isthmus and p = 0.005, for the left medial orbitofrontal cortex). Antidepressants and antipsychotics exposure did not affect the results. Discussion: Structural and neurochemical abnormalities (suggestive of loss of neuronal viability and impaired membrane integrity) in brain regions involved in affective regulation and in fronto-limbic connections were found in unipolar psychotic MDD in comparison with matched non-psychotic patients and controls. These findings were not explained by the severity of the depressive episode and were associated with the presence of psychotic symptoms. The results suggest that MDD might not be regarded as homogeneous in terms of underlying biological features and that specific pathophysiological aspects might underlie the different clinical types of MDD.

Risk factors for the occurrence of schizophrenia-like psychosis in patients with temporal lobe epilepsy

Rudá Alessi1, Karenina Goldberg1, Natascha Fonseca1, Katia Couto1, Sílvia Vincentiis1, Kette Valente1

1Instituto de Psiquiatria, Faculdade de Medicina da Universidade de São Paulo, São Paulo, SP, Brasil


Background
: Patients with partial epilepsy, mostly with temporal lobe epilepsy due mesial temporal sclerosis (MTS), present a higher incidence of mood disorders and psychosis, when compared both to general population and to other epileptic syndromes. Determination of electroclinical profiles that could help predict the occurrence of psychiatric disorders (PD) in these patients might have a positive impact on their treatment and prognosis. Our study aimed to identify electroclinical risk factors for the occurrence and type of psychosis in a group of patients with mesial temporal sclerosis (MTS). Methods: The study included patients with epilepsy and uni or bilateral MTS, and excluded patients with: other lesions besides MTS, double pathology, or extratemporal ictal onset. All patients underwent psychiatric evaluations (structured questionnaire) and were classified according to DSM IV and ICD 10. Clinical epilepsy variables were: onset age, duration, presence of TCGS, seizure frequency, polytherapy, previous status, complex febrile seizures and laterality (determined by MRI) and epileptogenic zone (determined by interictal and ictal EEG). Results: We evaluated 63 patients (34 [47.2%] male) with mean age of 39,1 years. Left MTS occurred in 35 (48.6%), right MTS in 32 (44.4%) and bilateral MTS in 05 (6.9%). Out of these 27 (37.5%) presented mood disorders, 23 (31.9%) psychosis. Thirty-four (47.2%) patients were on psychoactive medications. Previous or current PD were absent in 22 (30.55%). Patients with psychoses had longer duration of epilepsy (mean 32.21 ys) when compared to controls (26.26 ys) and patients with depression (24.76 ys) (p = 0.046). EEG epileptiform activity on right temporal lobe (p = 0.024) were significantly associated with an increase risk for psychosis. Other clinical variables did not differ among groups. Discussion: This study confirms that patients with MTS have a high prevalence of mood disorders and psychosis and displayed differences in the electroclinical profile. Most patients with MTS and psychosis presented right-sided changes in both MRI and EEG (interictal and ictal findings). Although correlations between laterality and PD are controversial, the present study is relevant because other possible factors, related to the development of such disorders were taken into account. Longer duration of epilepsy was related to MTS with psychosis, a finding in accordance with at least two current theories explaining this comorbidity.

Obsessive-compulsive symptoms and disorder in patients with schizophrenia treated with clozapine or haloperidol


Antonio R. Sa
1, Ana G. Hounie2, Aline S. Sampaio2, Euripedes C. Miguel2, Helio Elkis1

1Programa de Esquizofrenia, Departamento de Psiquiatria, Faculdade de Medicina da Universidade de São Paulo, São Paulo, SP, Brasil/2Programa de Transtorno Obsessivo Compulsivo, Departamento de Psiquiatria, Faculdade de Medicina da Universidade de São Paulo, São Paulo, SP, Brasil

Background
: The presence of obsessive-compulsive symptoms (OCSs) in patients with schizophrenia has been described since the 19th century, long before the advent of psychotropic medications. However, the reports of “de novo” and worsening of OCSs in patients with schizophrenia have increased in the last decades and maybe more frequent in refractory patients. The aim of our study was to investigate the prevalence of OCD/OCSs in patients with schizophrenia treated with clozapine or haloperidol. We hypothesized that refractory patients using clozapine would have a higher prevalence and severity of OCSs and OCD when compared to patients treated with haloperidol. Methods: The sample was comprised by patients who met diagnostic criteria for schizophrenia according of the DSM-IV. Patients in use of clozapine or haloperidol were recruited from the outpatient clinic for refractory schizophrenia at the Department and Institute of Psychiatry, University of São Paulo Medical School (FMUSP). Patients had to be stable on their dose of clozapine or haloperidol for 6 months before the interview. The final sample comprised 60 patients (45 men and 15 women), 40 of them using clozapine and 20 using haloperidol. The Structured Clinical Interview for DSM-IV Axis I disorders - patient edition was used for the diagnosis of schizophrenia and OCD. All subjects completed the Yale-Brown Obsessive-Compulsive Scale (Y-BOCS) [25] to rate the for OCD symptoms. The severity of schizophrenia symptoms was rated by the Positive and Negative Syndrome Scale (PANSS), and the Clinical Global Impression (CGI). Results: The prevalence of OCD in patients taking clozapine was 20%, whereas the prevalence of patients taking haloperidol was 10%, although this difference was not statistically significant (P = .540). However, patients using clozapine showed higher severity of OCSs than patients using haloperidol (P = .027) did. When schizophrenia patients were divided according to the presence or absence of OCD or OCSs, patients with schizophrenia and OCD or OCSs showed higher severity of schizophrenia symptoms when compared to those with schizophrenia without OCD and OCSs (p = .002). Severity of symptoms (PANSS total score > 70) and the use of antidepressants were predictors of the presence of OCSs or OCD. Schizophrenia patients taking clozapine had higher severity scores both in obsessive-compulsive and schizophrenia rating scales. Discussion: Although the prevalence of OCS or OCD was similar in the groups taking clozapine or haloperidol, patients using clozapine had higher severity in the Y-BOCS scores. These results support an association between the exacerbation of obsessive-compulsive phenomena and the use of clozapine. Our data also support the notion that the presence of OCD or OCSs is associated to higher severity of schizophrenia, information that should make clinicians especially attentive while taking care of these patients. Reference: Sa AR, Hounie AG, Sampaio AS, Arrais J, Miguel EC, Elkis H. Obsessive-compulsive symptoms and disorder in patients with schizophrenia treated with clozapine or haloperidol. Compr Psychiatry. 2009;50(5):437-42.

Oral Session 3 – Neurochemistry


Gone to pot”: evidence from laboratory studies with -9-THC

Deepak D’Souza
1,2,3, Richard Sewell1,2,3, Rajiv Radhakrishnan1,2,3, Patrick Skosnik1,2,3, Mohini Ranganathan1,2,3

1VA Connecticut Healthcare System, Schizophrenia Research Program, West-Haven, CT, United States/2Clinical Neuroscience Research Unit, Connecticut Mental Health Center, New Haven, CT, United States/3Department Psychiatry, Yale University School of Medicine, New Haven, CT, United States

Background
: Recent advances in knowledge about cannabinoid receptor function have renewed interest in the association between cannabis and psychosis. Converging lines of evidence suggest a relationship between cannabinoids and psychosis. Laboratory studies with delta-9-tetrahydrocannabinol (THC) have been a useful approach to investigate this relationship. Furthermore, cannabis is frequently used and misused by individuals with schizophrenia – and while cannabis appears to have a negative impact on the course and expression of schizophrenia, individuals with schizophrenia report deriving “benefits” from its use. Laboratory studies with THC may be useful in understanding the effects of cannabinoids in individuals with schizophrenia. Methods: We have characterized the dose-related behavioral, subjective, endocrine, electrophysiological and cognitive effects of intravenous THC in more than 250 healthy individuals in a series of double-blind, randomized, placebo-controlled laboratory studies conducted over the past 15 years. A range of doses (1-5 mg) of THC given at varying rates of infusion (5-20 minutes) have been studied. The sample has included healthy individuals, light users of cannabis and individuals with schizophrenia. The effects of THC on schizophrenia-relevant outcomes were measured including psychosis (PANSS) and perception, subjective effects, top-down processing (“babble” task), memory, attention, executive function, temporal processing, event related potentials (P300) and neural synchrony (ASSR). Furthermore, the influence of dopaminergic and GABAergic function on the THC response was characterized by studying the interactions of THC with haloperidol and iomazenil, respectively. Finally, the effects of CBD on the THC response are being investigated. Results: THC produces an array of transient schizophrenia-like positive and negative symptoms, perceptual alterations, verbal memory deficits, attentional deficits, working memory deficits and psychophysiological abnormalities in healthy individuals. THC also exacerbates symptoms in individuals with schizophrenia. Haloperidol pretreatment does not appear to attenuate the effects of THC and Iomazenil pretreatment may increase the vulnerability to THC. The effects of CBD on the THC response are not clear. Discussion: Cannabinoids can produce a range of transient schizophrenia-like phenomena. However, why some individuals are more vulnerable to these effects is not fully understood. Genetic factors and previous exposure to cannabis may influence the response to ?-9-THC in the laboratory, and these factors will be discussed. 

Differential metabolic profile in first episode psychosis supports the glutamate theory for schizophrenia

Linda Scoriels1, David J. Grainger2, Emmeline Goodby1, Anna Dean1, Pradeep J. Nathan1, John Suckling1, Belinda R. Lennox1, Edward T. Bullmore1, Peter B. Jones1

1Department of Psychiatry, University of Cambridge, Cambridge, United Kingdom/2Department of Medicine, University of Cambridge, Cambridge, United Kingdom

Background
: Some metabolic dysregulations are inherent to psychotic disorders. Metabolomics – a new technique that analyses the complete collection of metabolites produced by an organism – has led to the discovery of metabolites in post-mortem brains and peripheral blood in schizophrenia. We were interested in the identification of metabolic compounds in peripheral blood that allow the identification of individuals with a first episode of psychosis (FEP), amongst their first-degree relatives and healthy unrelated controls. The identification of metabolic endophenotypes in psychotic disorders may support diagnosis and treatment and increase the currently limited understanding of the pathophysiology of these disorders. Methods: 1H-NMR spectroscopy was applied on serum samples from 34 FEP patients, 33 relatives and 35 controls. Principal component (PCA) and partial least square (PLS) analyses were used to analyse the data. Human Metabolome Database and graphical analyses were performed to identify metabolic candidates. Results: Models built with 75% of the data showed a statistically significant metabolic segregation according to group (Chi2 = 23.44, p = 0.000008). However, external validation with the remaining 25% of the data did not reach significance (p = 0.24). Analysis of metabolic candidate compounds indicated an over-expression of NMDA R antagonist, metabolites involved in respiration pathway and compounds typically found in petrol. Moreover, agonists of the NMDA R, namely glycine and D-serine, and metabolites involved in the anabolism and catabolism of those via the methionine metabolism were suggested to be under-expressed in FEP patients. Discussion: Models enabled the identification of differential metabolites segregation between FEP patients, their relatives and controls. This segregation consolidated the idea of an endophenotype. The under-expression of NMDA R co-activators in FEP patients is consistent with one of the theories explored to explain the neurophysiopathology of schizophrenia.


Plasma oligopeptidase activity is lower in schizophrenic patients compared to healthy controls

Ary Gadelha1,2, Mauricio F. M. Machado3, Camila M. Yonamine2, Vitor Oliveira3, Rodrigo A. Bressan1,2, Mirian A. F. Hayashi2,3

1Programa de Esquizofrenia, Universidade Federal de São Paulo, São Paulo, SP, Brasil/2Laboratório Interdisciplinar de Neurociências Clínicas, Universidade Federal de São Paulo, São Paulo, SP, Brasil/3Departamento de Farmacologia, Universidade Federal de São Paulo, São Paulo, SP, Brasil


Background
: Ndel1 is an oligopeptidase preferentially expressed in neurons with ability to cleave endogenous peptide substrate as dynorphin, neurotensin (NT) and bradykinin (BK). Interestingly, B2 BK-receptors and dynorphin have been correlated with neurite outgrowth in NGF-induced PC12 cells differentiation to neurons, while the other substrate NT has been implicated in pathophysiology of schizophrenia (SCZ). Moreover, another oligopeptidase named POP was described to be decreased in plasma of schizophrenic patients, leading this enzyme to be considered as a significant drug target for the treatment of numerous diseases and mental neuropsychiatric diseases, such as post-traumatic stress disorder, depression, and also SCZ.
The neurite outgrowth in differentiating PC12 cells is highly dependent on Ndel1 and Disc1 interaction. Disc1 is an enzyme implied by several lines of evidence to SCZ. Our group showed that a cooperative interaction between Disc1 and Ndel1 was found to regulate neuronal morphogenesis and positioning during neuronal integration, leading us to suggest that Ndel1 enzymatic activity may play a role in the etiology of SCZ. Methods: Taken together, aiming to evaluate Ndel1 activity as a tool to differentiate patients and controls we have evaluated 92 patients that fulfilled DSM IV criteria for SCZ assessed with the Structured Diagnostic Interview (SCID) by experienced interviewers with good inter-rater reliability. All patients have been followed in Schizophrenia Program (PROESQ) of UNIFESP, and 2 experienced clinicians confirmed the diagnosis. We have so far 41 healthy controls matched for sex, age and educational level. They have no personal psychiatric diagnosis assessed by SCID and no familial diagnosis of psychosis. All participants provided peripheral blood samples for the Ndel1 activity assay. Results: It was observed a lower mean value for the enzymatic activity in the patients group compared to healthy controls. This difference was statistically significant t (131) = 3,006 with a p value of 0.003. For t-test, the enzymatic activity values were converted to z scores once they did not follow a normal distribution. We then categorized patients and controls by high and low Ndel1 activity, according to patients mean, and performed a logistic regression model correcting for age and sex. We found a significant association between the lower Ndel1 level and to be a patient (p value < 0,001, Exp[B] 7,242; 95% CI 2,412-21,740, and Nagelkerke R Square value of 0,239). Discussion: We suggest that Ndel1 activity may be a useful tool to differentiate SCZ patients and normal controls. This is the first study to investigate Ndel1 enzymatic activity in humans in vivo. The key role of Ndel1 activity in neurodevelopmental processes makes it a promising target to further studies not only as a biomarker, but also as a potential target for drug development.

D1 and D2 dopamine receptors modulate the contextual fear conditioning deficit presented by SHR: strenghthening this animal model of emotional processing deficits in schizophrenia


Mariana B. Calzavara1,2, Camila M. Santos1,2, Wladimir A. Medrano1, Raquel Levin1,2, Vanessa C. Abílio1,2

1Departamento de Farmacologia, Universidade Federal de São Paulo, São Paulo, SP, Brasil/2Departamento de Psiquiatria, LINC, Universidade Federal de São Paulo, São Paulo, SP, Brasil

Background
: We have described that spontaneously hypertensive rats (SHR) present a contextual fear conditioning (CFC) deficit that is specifically reverted by antipsychotics and potentiated by proschizophrenia manipulations. Based on these findings, we suggested that this could be a useful animal model to study abnormalities in emotional processing in schizophrenia. Recently, we also have observed that inactivation of nucleus accumbens as well as activation of prefrontal cortex attenuated the deficit presented by SHR. These results are in accordance with the proposed overactivity of the mesolimbic system and hypoactivity of prefrontal cortex underlying the pathophysiology of schizophrenia. More specifically, mesolimbic overactivity seems to be mediated by D2 receptors while D1 receptors seems to be altered in the prefrontal cortex. In this regard, the aim of this work was to investigate the role of dopaminergic transmission via D1 and D2 receptors in the prefrontal cortex and nucleus accumbens, respectively, in the CFC deficit presented by SHR. Methods: Adult male wistar rats and SHR were implanted bilaterally with stainless steel guide cannulae using the following stereotaxic coordinates in relation to Bregma: 1) Prefrontal cortex (PFC - prelimbic area) - AP +3.2, LAT 0.6 and V -4.0; 2) Nucleus Accumbens (Shell – NACc) – AP +2.7, LAT 1.4 and V -7.0. Quinpirole or raclopride (D2 receptor agonist and antagonist, respectively) were injected into the nucleus accumbens (1 ug/0,5 uL/side) and SKF38393 and SCH23390 (D1 receptor agonist and antagonist, respectively) were injected into the prefrontal cortex (1 ug/0,5 uL/side). Thirty minutes later, the rats were submitted to the training session of CFC task. At this session, the rats were placed in a dark chamber with a grid floor. After 150 seconds, 0.4-mA footshocks lasting 5 seconds were applied every 30 seconds for the subsequent 150 seconds. The contextual conditioning test (test session) was performed 24 hours after the training. Each animal was placed in the same dark chamber, without receiving footshocks. The freezing duration (defined as complete immobility of the animal, with the absence of vibrissae movements and sniffing) was quantified during 5 minutes. Results: D2 receptors blockade in the nucleus accumbens as well as D1 receptors stimulation in the prefrontal cortex attenuated the deficit presented by SHR. Discussion: These results reinforce the intersections between CFC deficit in SHR and emotional processing abnormalities in schizophrenia.

Prenatal exposure to cigarette smoke causes persistent changes in the oxidative balance and in DNA structural integrity in rats submitted to the animal model of schizophrenia

Felipe D. Pacheco1, Daiane B. Fraga1, Pedro F. Deroza1, Fernando V. Ghedim1, Amanda V. Steckert1, Renata D. De Lucca1, Alexandre Silverio1, Andreza L. Cipriano1, Daniela D. Leffa1, Gabriela D. Borges1, João L. Quevedo1, Ricardo A. Pinho1, Vanessa M. Andrade1, Felipe Dal Pizzol1, Alexandra I. Zugno1

1Universidade do Extremo Sul Catarinense, Criciúma, Santa Catarina, Brasil

Background
: Epidemiological studies have indicated that prenatal exposure to environmental insults can bring an increased risk of schizophrenia. The aim of our study was to determine biochemical parameters in rats exposed to cigarette smoke (CS) in the prenatal period, evaluated in male adult offspring submitted to animal model of schizophrenia induced by acute subanesthetic doses of ketamine (5 mg/kg, 15 mg/kg and 25 mg/kg). Methods: Pregnant female Wistar rats were exposed to 12 commercially filtered cigarettes per day, for 28 days. We evaluated the oxidative damage in lipids by formation of thiobarbituric acid reactive species (TBARS) and the oxidative damage to the proteins by carbonil groups content, in brain structures. DNA damage was evaluated by single cell electrophoresis (Comet Assay) in peripheral blood. The data were analyzed by Student’s t-test or by one-way ANOVA followed by the Tukey test when the F-test was significant (p < 0.005). Results: In the prefrontal cortex, hippocampus and striatum there was an increase of lipid peroxidation among the CS group rats, compared with the saline group. The CS alone presents a persistent effect to the protein oxidation in all structures. Rats exposed to CS in the prenatal period presented increased DNA damage in peripheral blood. In prefrontal cortex, the animals from CS group which were submitted to acute ketamine 5 mg/kg and 15 mg/kg presented an increased lipid peroxidation. In hippocampus, 15 mg/kg and 25 mg/kg of ketamine, in rats non-exposed to CS, induced an increased lipidic peroxidation compared with the saline group. In addition, lipidic damage was found in CS and ketamine exposed rats in all of the doses, in hippocampus. In the striatum, an increase of lipid peroxidation was found in non-CS rats which received acute 25 mg/kg of ketamine and in all of the CS-ketamine groups, compared with saline. Discussion: Biochemical changes by acute ketamine were inconsistent, not additive to CS exposure. Prenatal exposure to CS is related to increased oxidative stress in brain structures involved in schizophrenia.


Neonatal hypoxia enhances dopamine-mediated effects of cocaine repeated administration in adult mice

Victor P. Ricardo
1,2, Sônia R. Kameda1, Rafael Wuo-da-Silva1, Daniela F. Fukushiro1, Vânia D’Almeida3, Sérgio Tufik3, Roberto Frussa-Filho1

1Departamento de Farmacologia, Universidade Federal de São Paulo, São Paulo, SP, Brasil/2Curso de Biomedicina, Universidade Paulista, São Paulo, SP, Brasil/3Departamento de Psicobiologia, Universidade Federal de São Paulo, São Paulo, SP, Brasil

Background
: Schizophrenic patients present several behavioral alterations, including greater prevalence of substance use disorders.
A large number of epidemiological studies have now confirmed that obstetric complications clearly associated with fetal or neonatal hypoxia confer increased risk for schizophrenia. In this context, the objective of this study was to verify the long-term effects of neonatal hypoxia on cocaine-induced behavior. Methods: Reactivity to novelty, cocaine-induced behavioral sensitization and locomotor conditioned response (animal models of drug abuse) were used to evaluate the behavior of fourteen post-hypoxic and fourteen control female adult mice. This work was approved by the Research Ethics Committee of São Paulo Federal University, number: 0776/06. Results: Neonatal hypoxia produced an increase in the reactivity to a novel environment (4726.14 ± 202.39 and 4006.62 ± 239.64 for neonatal hypoxia and control groups, respectively), an enhancement in cocaine-induced behavioral sensitization (7735.69 ± 280.22 and 6395.69 ± 347.78 for neonatal hypoxia and control groups, respectively) and facilitation in the establishment of a conditioned locomotor response (5165.38 + 233.22 and 4331.25 + 311.95 for neonatal hypoxia and control groups, respectively). Discussion: Locomotor activity in rodents has been extensively related to the activity of the mesolimbic dopaminergic system, which plays a critical role in both schizophrenia and drug dependence. Within this context, the present study supports the possibility that schizophrenic patients present an increase in the prevalence of substance use disorders due to an increase in underlying patterns of corticolimbic abnormalities responsible for schizophrenic syndromes affecting the function of primary motivational circuitry, namely the mesolimbic dopaminergic system, and underscores the need for further behavioral investigation on the impact of neonatal hypoxia on drug responses using alternative dosing schedules and alternative addictive drugs. Financial support: FAPESP, FADA, CNPq, AFIP.

Oral Session 4 - Neuroimaging


Brain structure and the prediction of outcome in first-episode schizophrenia-spectrum disorders and affective psychosis: a population-based study


Pedro G. P. Rosa
1, Maristela S. Schalfelberger2, Fabio L. S. Duran1, Luciana C. Santos1, Paulo R. Menezes1, Márcia Scazufca1, Marcus V. Zanetti1, Robin M. Murray3, Geraldo F. Busatto1

1Departamento de Psiquiatria, Faculdade de Medicina da Universidade de São Paulo, São Paulo, SP, Brasil/2Departamento de Psiquiatria, Faculdade de Medicina da Universidade de São Paulo, São Paulo, SP, Brasil/Departamento de Neurociência e Comportamento, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, SP, Brasil/3Institute of Psychiatry, King’s College, London, United Kingdom

Background
: The study of the prediction of outcome among subjects with first-episode of psychosis employing MRI has brought misleading evidence to discussion. Also, cognitive impairment in subjects with psychoses is receiving particular attention, especially in schizophrenia-spectrum disorders, and cognitive impairment is now considered one of the core features of these illnesses and perhaps the dimension most associated with outcome in those patients. Thus, we hypothesize that cognitive impairment may be the outcome measure most associated with structural brain abnormalities found at the first-episode of psychoses. Methods: We employed structural MRI on a large first-episode psychosis (FEP; N = 96) sample with subjects with schizophrenia-spectrum disorders (N = 55) and affective psychosis – bipolar disorder (N = 23) and psychotic depression (N = 18), recruited using a population-based design in São Paulo, Brazil. The sample’s outcome was evaluated after a median period of one year and consisted on symptoms severity (PANSS), cognitive measures (verbal fluency and forward and backward digit spans) and also general disability evaluation (WHO-DAS). We evaluated the lateral ventricles (using a region of interest approach) and the whole and regional gray matter (GM) volumes (using voxel-based morphometry with SPM) at the baseline as predictive of the outcome measures assessed at the 1-year follow-up. Results: Brain regions measured at baseline were found to be associated with the outcome measures in the overall FEP group and also when the schizophrenia-spectrum subgroup and the affective psychosis subgroup were evaluated in separate. Mainly, frontal and temporal cortices GM volumes (temporal gyri and medial temporal structures) were positively associated with outcome measures, in particular with the performance on cognitive tasks. GM volumetric measures of the pre-cuneus, the insula and the cerebellum were also associated with outcome. Particularly, the affective psychosis subgroup showed more robust associations of GM volumes with outcome measures than the schizophrenia-spectrum subgroup. Furthermore, temporal horns measures were negatively correlated with digit spans’ performances in the FEP group, in the affective psychoses and in the schizophrenia-spectrum psychoses subgroups analyses. None of these findings could be attributed to confounding factors, such as age, sex, interval between evaluations, outcome measures at baseline and antipsychotic intake. Discussion: Brain structure at the moment of the first-episode of psychosis was associated with outcome measures assessed after 1 year, and this association was present in affective psychosis patients as well as in patients with schizophrenia-spectrum psychosis. The predominance of findings on frontal and temporal regions is compatible with the fronto-temporal disconnectivity hypothesis previously postulated for the pathophysiology of psychoses. Furthermore, the predominance of positive findings in the association between GM and cognitive tasks is in agreement with the recent attention given to such dimension of symptoms in subjects with psychoses. Finally we consider that, in the future, neuroimaging techniques, together with other biological markers, may be useful as a tool to clinicians.

Corpus callosum volumes in recent-onset schizophrenia predict outcome of positive symptom severity


Mauricio H. Serpa1, Maristela S. Schaufelberger1, Pedro G. Rosa1, Fábio L. S. Duran1, Luciana C. Santos1, Robin M. Muray2, Márcia Scazufca1, Paulo R. Menezes1, Geraldo F. Busatto1

1Universidade de São Paulo, São Paulo, SP, Brasil/2King’s College London, London, United Kingdom

Background
: Predicting the prognosis of patients with schizophrenia (SZ) is of critical importance. No valid biomarkers have been made available till now. The corpus callosum (CC) consistently displays alterations in morphostructure and functioning in patients at early disease
stages. Theoretical models of SZ highlight the relevance of CC to the abnormalities of information processing. We investigated whether volumetric CC measurements at the onset of psychosis could predict prognosis after one year. Methods: Patients were enrolled after contact due to the emergence of psychotic symptoms. Inclusion criteria were: diagnosis of functional psychosis (SCID/DSM-IV) and age between 18 and 50 years. Exclusion criteria: neurological disease or medical diseases that could affect the CNS, history of head injury, moderated to deep mental retardation, and contraindications for MRI scanning. Outcome measures: the Positive and Negative Syndrome Scale (PANSS), the Psychiatry Disability Assessment Schedule, cognitive performance, remitting or non-remitting course, and number of psychotic episodes. MRI datasets were obtained using two 1.5T scanners. Voxel-based linear correlation analyses of CC volumes were carried out with outcome measures described above. All analyses included the total amount of WM in the brain and age as confounding covariates. Also, in each analysis, two out of the following three additional confounding variables were always included: gender, number of days of antipsychotic use prior to MRI scanning, and the baseline score for the variable under testing. Only clusters that survived family-wise error correction for multiple comparisons at the voxel-level level
of P < 0.05 are reported. Results: The volumes of anterior and medium CC portions correlated positively with PANSS positive scores at follow-up in the three possible analyses (number of voxels in each cluster ranging between 112-167). No other correlations were found.
Discussion: Our findings show that SZ patients with higher volumes of the anterior and middle CC portions at the onset of psychosis are more likely to present positive symptoms at 1 year after psychosis onset. In previous studies, measures of CC volume and integrity were positively related to positive symptoms. Such findings corroborate the theories which propose that positive symptoms of SZ could be mediated by excessive callosal transfer of information – a larger CC, composed of less affected fibers, would render a patient more liable to presenting positive symptoms by promoting the inter-hemispheric transfer of information that is processed aberrantly due to intra-hemispheric neuropathological changes. Clinical outcome of SZ subjects may depend not only on the presence of specific regional brain abnormalities but also on the
interplay between these and the degree of anatomical and functional integrity of neural pathways involved in information transfer.

Structural brain changes in first-episode schizophrenia: a 4-5 year follow-up study using MRI

Maristela S. Schalfelberger1, Pedro G. P. Rosa2, Markus V. Zanetti2, Fabio L. S. Duran2, Paulo R. Menezes3, Marcia Scazufca3, Robin M. Murray4, Geraldo F. Busatto2

1Departamento de Psiquiatria, Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP, Brasil/Departamento de Neurociências e Comportamento, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, SP, Brasil/2Departamento de Psiquiatria, Faculdade de Medicine, Universidade de São Paulo, São Paulo, SP, Brasil/3Departamento de Medicina Preventiva, Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP, Brasil/4Institute of Psychiatry, King’s College London, London, United Kingdom

Background
: The presence of progressive structural brain changes over the first years of disease in first-episode schizophrenia patients is still controversial. The supposed progression of brain abnormalities in these patients may be associated with outcome and with antipsychotic exposure. This epidemiological-designed study aimed to determine if FES patients show progression of gray matter (GM) or lateral ventricles (LV) changes in comparison to controls after a follow-up of 4 years, and also to investigate possible factors associated with longitudinal changes. Methods: Longitudinal population-based study performed in São Paulo – Brazil. Longitudinal analyses of GM matter volume using voxel-based morphometry with SPM and LV volume using Region of Interest (ROI) methods were performed in 32 FES and 34 healthy controls gathered from the same geographical region 4-5 years after the baseline measures. Outcome measures were assessed by clinical course of symptoms as described by the DSM-IV and by global functioning assessed by the GAF scores. Results: Groups did not differ in sociodemographic characteristics. Patients did not differ from controls regarding GM changes over time, but those that remained psychotic and had lower global functioning over the follow-up period had GM concentration reduction in the left insula and in the left superior temporal gyrus in comparison to controls. LV volumes (without temporal horns) increased over time in both groups, but this analysis revealed no group by time interaction. Medication status had no effect on either GM or LV volumetric changes. Discussion: Our findings suggest that a poor outcome, with chronic symptoms and a poor global functioning over 4-5 years after the first episode of psychosis is associated with brain abnormalities progression in brain regions which showed GM reduction at baseline (Schaufelberger et al. 2007). These results are in agreement with our 1-year follow-up evaluation (Schaufelberger et al. 2010) and with other previous studies that associated poor outcome with greater brain abnormalities progression, and suggest that the progressive hypothesis in schizophrenia is probably not valid to all subjects that suffer from this illness. The baseline comparison of the subjects that completed the 4 years of follow-up yielded similar results, although in a lesser extend, showed in the full-group cross-sectional analyses of baseline scans (122 patients, 62 of those with schizophrenia, and 94 controls), what suggests that the attrition rate probably had little influence on the results presented here.


Longitudinal follow-up of cavum septum pellucidum and adhesio interthalamica alterations in first-episode psychosis: a population-based MRI study

Clarissa Trzesniak1,2, Maristela S. Schaufelberger3, Robin M. Murray2, Philip K. McGuire2, Jaime E. C. Hallak1, Fabio L. S. Duran3, Luciana C. Santos3, Marcia Scazufca3, Paulo R. Menezes3, José A. S. Crippa1, Geraldo F. Busatto3

1Departamento de Neurociências e Comportamento, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, SP, Brasil/2Department of Psychosis Studies, Institute of Psychiatry, King’s College London, London, United Kingdom/3Departamento de Psiquiatria, Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP, Brasil

Background
: Among the etiological hypotheses for the manifestation of psychosis, the neurodevelopmental model is one of the most prominent. Examples of these abnormal developments are the presence of cavum septum pellucidum (CSP) and the absence of adhesio interthalamica (AI) later in life. The CSP is a cavity located between the lateral ventricles, which is present when the two laminae of the septum pellucidum fail to fuse by the age 3-6 months. In turn, the AI is a grey matter bridge that connects both thalami and usually fuses around the 14th week of the gestation. Structural magnetic resonance imaging (MRI) studies have showed that the incidence of both large CSP (= 6 mm in the anterior-posterior axis) and absent AI is higher in psychosis, though there are several negative results. This inconsistency is likely due to the lack of standardization of the methodology among the studies and selection bias of the samples. The aim of this current investigation was to conduct the first longitudinal and population-based MRI evaluation of the presence and size of the CSP and AI in a large sample of subjects with first-episode psychosis (FEP) recruited in the city of São Paulo, Brazil. Methods: FEP patients (n = 122) – subdivided into schizophrenia group (n = 62); affective disorders (n = 49) and psychosis not otherwise specified (n = 11) according to the DSM-IV, were matched by age, sex and handedness to 94 healthy controls, who were the next-door neighbours from the patients. After 15.0 (± 5.4) months, 80 FEPs and 52 controls underwent a second MRI scan in order to assess possible brain morphological changes over time. Statistical significance was set at P < 0.05.
Results: We found significant reductions in the length of the AI in schizophrenia FEP related to affective disorder (intermediate value) and healthy volunteers (longer length) at the baseline, and no differences in any measure of the CSP. In contrast, there was a diagnosis-by-time interaction for the length of the CSP, showing more prominent increase for this measure in the psychosis group than in controls. There was an involution of the length of the AI over time for all groups, but no diagnosis-by-time interaction was seen. Finally, when all the subjects were pooled together, male individuals showed higher prevalence of large CSP and shorter AI than females, regardless of the diagnosis status. Discussion: Our findings suggest that the CSP per se may not be linked to the neurobiology of emerging psychotic disorders, although may be somehow related to the progression of the disease. It also corroborates the view that progressive structural brain changes occurring from the earliest phases of the illness are present in psychosis. On the other hand, the fact that the AI length was already shorter at the onset of the disorder supports the neurodevelopmental model of schizophrenia and suggests that an alteration in this grey matter junction may be a risk factor for developing psychosis. Our results further support that there may be a continuum for psychosis in the way that the length of the AI is present, being the schizophrenia-type the most affected among the psychoses.

Neuroanatomical pattern classification of MRI data: discrimination of different psychotic disorders at the first episode

Marcus V. Zanetti1, Maristela S. Schaufelberger1, Jimit Doshi2, Yangming Ou2, Bilwaj Gaonkar2, Luiz K. Ferreira1, Paulo R.
Menezes3, Marcia Scazufca3, Christos Davatzikos2, Geraldo F. Busatto1


1Departamento de Psiquiatria, Universidade de São Paulo, São Paulo, SP, Brasil/2Department of Radiology, University of Pennsylvania, Philadelphia, PA, United States/3Departamento de Medicina Preventiva, Universidade de São Paulo, São Paulo, SP, Brasil

Background
: Neuroanatomical pattern classification is a powerful technique for image processing and analysis which allows both voxelwise group comparisons and classification of images at an individual basis. We aim to evaluate the diagnostic performance of support vector machine (SVM)-based complex morphological pattern classifiers to discriminate different non-affective and affective psychotic disorders at the first episode. Methods: Sixty-two patients with first-episode schizophrenia/schizophreniform disorder (SCH), 23 cases presenting with their first-episode of psychotic mania (bipolar I disorder, BD-I) and 19 individuals with psychotic major depressive disorder (MDD) were studied with 1.5 T structural magnetic resonance imaging (MRI), as well as 94 epidemiologically recruited controls. T1-weighted images were first registered to a common template through a high-dimensional mass-preserving routine. A multivariate classification method based on SVM was employed to identify the best set of morphological features that discriminate each diagnostic subgroup (SCH, BD-I & MDD) from the controls and from each other. The resulting “morphological signatures” were, then, applied at an individual basis using a leave-one-out cross-validation strategy. Measures of overall diagnostic accuracy, sensitivity and specificity were obtained with the use of a ROC curve. Results: Preliminary analysis revealed that the SVM-based classifier correctly differentiated psychotic BD-I patients from controls with an overall accuracy of 87%, 81% of sensitivity and 90% of specificity. Results regarding the multi-sample classification between SCH versus BD-I versus MDD versus controls are currently under analysis and will be presented at the time of the conference. Discussion: Non-linear, multivariate image analysis of brain MRI is able to detect subtle structural abnormalities even at an early stage of psychotic disorders. The high discriminative power of such methods suggests that the development of auxiliary diagnostic tools is feasible in the near future.


Functional disconnectivity and formal thought disorder in schizophrenia: integrating clinical, neuropsychological, neuroimaging and functional connectivity data

Silvia Maria Arcuri1,2,3, Edson Amaro2, Matthew R. Bromme4, Gilson Vieira2, João R. Sato2, Vincent Giampietro5, Steve S. C. Williams5, Koichi Sameshima2, Luiz Baccalá6, Michael J. Brammer5, Robin G. Morris7, Philip McGuire1

1Department of Psychosis Studies, King’s College Institute of Psychiatry, U. London, London, United Kingdom/2NIF – Grupo de Neuroimagem Funcional/LIM 44, Instituto de Radiologia, Universidade de São Paulo, São Paulo, SP, Brasil/3Projeto Esquizofrenia – Projesq, Instituto de Psiquiatria, Hospital das Clínicas, Faculdade de Medicina da Universidade de São Paulo, São Paulo, SP, Brasil/4Warwick Medical School, University of Warwick, Coventry UK and PCAG, Coventry, United Kingdom/5Department of Neuroimaging, King’s College Institute of Psychiatry, University of London, London, United Kingdom/6Escola Politécnica, Universidade de São Paulo, São Paulo, SP, Brasil/7Department of Psychology, King’s College Institute of Psychiatry, University of London, London, United Kingdom

Background
: Little is known of the pathophysiology of Formal Thought Disorder (FTD) in schizophrenia. We used a novel method (called Partially Directed Coherence – PDC) to analyse functional connectivity in fMRI data, in addition to results obtained from a sample of schizophrenic patients studied with neuropsychological tasks and traditional fMRI analyses. Methods: Forty DSM-IV schizophrenic patients (21 with, 19 without FTD) were compared to 20 healthy controls (HC) while performing executive verbal (VWMt) and visuo-spatial (VSWMt) working memory tasks. Groups were matched for IQ and clinical measures. Half of the sample was additionally studied using event-related fMRI task during a semantic decision task. Data Analyses: Psychological: using SPSS with Repeated Measures, co-varying the FTD score (from SAPS and SANS). FMRI: within each of the 3 groups (HC, NTD and FTD patients) using XBAM for within group activation and between group differences. The imaging data were analysed for functional connectivity using PDC within each group, including all activated clusters in the 3 groups; HC, NTD and FTD (respectively 33, 49 and 26 areas), without a priori assumptions or order limitations. The PDC connectivity strength data for each group was plotted. A cut-off point for the connectivity strength > or = 0.10 for NTD and 0.05 for FTD was chosen to demonstrate the main pathways. Results: Neuropsychology: Main effects for group and for FTD were observed for the VWMt: schizophrenic patients showed impaired performance relative to HC (p = 0.38), and the FTD score was associated with poorer performance (p = 0.027). Performance on the VSWMt (Golf) showed similar results, with main effects of group and FTD (respectively p < 0.001 and p = 0.001). There was also a main effect of group (p = 0.001) and of FTD (p = 0.021) on strategy formation during VWMt, and of group (p = 0.003) on strategy formation during the VSWMt. Imaging: During the semantic decision task, FTD patients showed attenuated activation relative to controls in the Inferior Frontal, Pre Central, Superior, and Middle Temporal, and Fusiform gyri, and in the Insula, caudate, thalamus and Cerebellum, bilaterally. There was also differential engagement of the right Posterior Cingulate, Lingual, Cuneus, and Striate cortex. Regions directly or indirectly connected to these areas were not activated in the FTD group. They thus had a different set of connectivity nodes and pathways, observed in the PDC analysis, relative to controls. NTD patients showed more activated areas than both controls and FTD, including Inferior Frontal, Pre Central bilaterally, left Superior and Middle Temporal, Anterior Cingulate, Cuneus, Fusiform gyri, and Cerebellum, bilaterally. There was also engagement of basal ganglia nuclei, right Lingual and left Striate cortex. Direct contrast between NTD and FTD revealed several differences in brain activation. NTD also had a different set of connectivity nodes and pathways, observed in the PDC analysis relative to controls and FTD. They had a scattered data for connectivity strength, with a few greater values relative to controls but most of them weaker, in a pattern more similar to FTD than to controls. Discussion: Connectivity maps observed in FTD patients and HC were clearly different. The map in controls probably corresponds to a network associated with the execution of a semantic decision task. The impaired performance of FTD patients on semantic and working memory tasks may be related to a failure to activate nodes within this network, in the appropriate sequence. In addition to areas traditionally associated with language, this network involves regions involved in executive processing, suggesting that executive dysfunction is a contributor to FTD in schizophrenia.

Faulty suppression of irrelevant material in thought disordered schizophrenic patients associated with attenuated frontal and temporal brain activation


Silvia M. Arcuri1,2,3, Matthew R. Broome4, Vincent Giampietro5, Edson Amaro Jr.2, Tilo T. Kircher6, Steven C. R. Williams5, Christopher Andrew5, Michael J. Brammer5, Robin G. Morris7, Philip K. McGuire1

1Department of Psychosis Studies, King’s College Institute of Psychiatry, U. London, London, United Kingdom/2NIF – Grupo de Neuroimagem Funcional/LIM 44, Instituto de Radiologia, Universidade de São Paulo, São Paulo, SP, Brasil/3Projeto Esquizofrenia – Projesq, Grupo de Pesquisa em Esquizofrenia, Instituto de Psiquiatria, Universidade de São Paulo, São Paulo, SP, Brasil/4Warwick Medical School, University of Warwick, Coventry UK and PCAG, Conventry, United Kingdom/5Department of Neuroimaging, King’s College Institute of Psychiatry, University of London, London, United Kingdom/6Marburg University, Marburg, Germany/7Department of Psychology, King’s College Institute of Psychiatry, University of London, London, United Kingdom


Background
: Formal Thought Disorder is a feature schizophrenia that manifest as disorganized, incoherent speech and is associated with a poor clinical outcome. This disabling phenomena often leads to social exclusion and diffculties in admittance to specialized treatment in public services. The neurocognitive basis of this symptom is unclear but it is thought to involve impairment in semantic processing classically described as a loosening of meaningful associations. Methods: Using a paradigm derived from the n400 event-related potential we examined the extent to which regional activation during semantic processing is altered in schizophrenic patients with Formal Thought Disorder. Ten healthy control (HC) and 19 acutely psychotic patients meeting DSM-IV criteria for schizophrenia (10 with – FTD and 9 without formal thought disorder – NTD) performed a semantic decision sentence task during an event-related functional magnetic resonance imaging experiment. Main effects of semantic constraint (Ct) and congruency, and the interaction of diagnosis and formal thought disorder on activation were estimated with analysis of variance. Imaging analysis included correct trials only. Psychopathology was assessed using SAPS and SANS. There were no significant between group differences in demographic and cognitive (Nart IQ) characteristics. Both subgroups of patients had similar clinical and psychopathological characteristics.
Results: Online Behaviour: Semantic constraint and semantic congruency both influenced RTs, with minimum values in trials with congruous endings and HCt stems (facilitation effect). The patients made more errors than controls, particularly those with FTD. Neuroimaging: a) HC:  Low relative to High Ct were associated with greater activation in the right inferior dorsal, the left orbital and right middle frontal cortices, the right posterior temporal cortex, bilateral anterior cingulate and the right precuneus. Congruent trials activated more than incongruent ones: the right orbital and left middle frontal cortices, left posterior temporal cortex, bilateral anterior cingulate and left precuneus.b) HC vs. Patients: Low vs. High constraint was associated with greater activation in controls than in patients in the orbital portions of the left inferior frontal cortex bilaterally and in the left middle temporal gyrus. Patients showed greater activation than controls in the right red nucleus, the right cuneus, the right middle frontal gyrus and the left insula. Congruent vs. incongruent sentences was associated with greater activation in controls than patients in the dorsal portion of the inferior frontal cortex bilaterally and cerebellum and in left angular gyrus and middle temporal gyri. Patients showed greater activation than controls in the right middle occipital gyrus. c) Specific FTD: FTD patients showed attenuated activation relative to HC in the Inferior Frontal Gyri bilaterally, left Middle Temporal, left Lingual Gyrus, left Precuneus and Cerebellum, bilaterally. Relative to NTD, FTD showed attenuated activation in the Middle Fontal Gyri and Anterior Cingulate bilaterally. FTD showed more activation than NTD in the Right Posterior Cingulate Cortex. Discussion: We found that the frontotemporal network normally engaged by a semantic decision task (confirmed by our experiment), was under activated in schizophrenia, particularly in patients with FTD. This network is implicated in the inhibition of automatically primed stimuli and impairment of its function interferes with language processing and contributes to the production of incoherent speech.

Oral Session 5 – Treatment & Healthcare

Traditional medical systems as sources of new psychoactive drugs: the case of the putative antipsychotic alstonine

Elaine Elisabetsky1,2, Viviane M. Linck1,2, Ana P. Herrmann1,2, Luciane Costa-Campos1, Christopher O. Okunji3, Maurice Iwu3

1Laboratório de Etnofarmacologia, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brasil/2Programa de Pós-Graduação em Ciências Biológicas: Bioquímica, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brasil/3International Centre for Ethno Medicine and Drug Discovery, Nsukka, Enugu State, Nigeria

Background
: Traditional (indigenous) and modern (western biomedical) medical systems evolved from diverse perceptions of reality, are related to different cosmovisions, and are thus often based on different paradigms. Within the context of drug development, the pharmaceutical industry and academic pharmacology mostly focus their interest in traditional medical systems on the use of plants processed as traditional medicines. The underlying understanding is that plants are known sources of bioactive compounds often with unique structures that may lead to innovative mechanism of action. Nevertheless, a closer understanding of claims of therapeutic outcomes from traditional practices may be useful to streamline further laboratory analysis: alleged outcomes can be used to form specific hypothesis of pharmacological properties. This presentation includes the ethnopharmacology data that lead to the identification of alstonine as a putative antipsychotic with an apparent innovative mechanism of action. Methods: During an ethnopharmacological expedition (February 1993) in Nigeria among the Igbo people, a visit to Dr C.O., a traditional psychiatrist, lead to the identification of a plat based preparation used to treat mentally ill patients. Though part of the treatment included culturally contextualized rituals, Dr C.O. treats patients with the plant medicine known in Igbo as ‘uhuma obi-nwok’ or ‘the heart of man’. Different posologies and plant preparations were described to be used according to the patient’s initial condition and during the course of treatment. In Dr. C.O. clinic the patients were visibly responsive to the environment stimuli and did not present signs of hypotension, suggesting that neither neuroleptics nor reserpine containing formulas were in use. Considering our interest in further laboratory analysis Dr. C.O provided 45 g of dried root powder from his stash, from which a crude ethanol extract (SP49000) was obtained. Results: SP49000 clearly showed an antipsychotic-like activity in various mouse models, while the chemical analysis revealed the indole alkaloid alstonine as the dominant component. Alstonine shows an atypical-like profile on mouse model correlated to positive (apomorphine and amphetamine-induced stereotypies; MK-801-induced hyperlocomotion, and amphetamine-induced lethality in grouped mice) and negative symptoms (MK801-induced social withdrawal), as well as cognitive deficits (MK801-induced working-memory deficit). Acute alstonine did not induce catalepsy or increased prolactin levels, and alstonine sub-chronic administration did not increased weigh gain or induce epileptic-like episodes.  However, alstonine seems to alter glucose metabolism in the same manner as clozapine. Though the mechanism of action underlying the antipsychotic-like effects of alstonine is yet to be fully understood, in vivo and ex vivo approaches indicate that 5HT2A/C receptors may be fundamental whereas D2 dopamine receptors direct blockade is not in place. Discussion: The identification of alstonine as a new antipsychotic candidate or as a molecular model for developing prototypic antipsychotics exemplifies the potential of ethnopharmacology as a tool for revealing psychoactive compounds. This approach based on the systematic observation of therapeutic properties, even if by personnel from a different medical tradition, may be of especial interest for diseases to which the pathophysiology is not clearly understood preventing a rational choice of molecular targets. Such is the case of schizophrenia, for which the necessity of innovative drug mechanism on better antipsychotics is unquestionable. Acknowledgments: CNPq.

Low recognition of refractory schizophrenia in the public mental health system in São Paulo – Brazil

Deyvis M. L. V. Rocha1,2, Ana S. A. Silveira1, Cecília Attux1, Claudiane S. Daltio1, Letícia A. Silva1, Camila Matsuzaka1, Rodrigo A. Bressan1,2

1Programa de Esquizofrenia (PROESQ), Universidade Federal de São Paulo, São Paulo, SP, Brasil/2Laboratório Interdisciplinar de Neuroimagem e Cognição – LiNC, Universidade Federal de São Paulo, São Paulo, SP, Brasil

Background: It is generally assumed that 20 to 30% of patients with schizophrenia do not respond adequately to conventional antipsychotics. These treatment-resistant (TR) schizophrenic patients represent a persistent public health problem, as they consume more resources allocated to medical care and frequent hospitalizations are necessary to control their symptoms. Treatment-resistant schizophrenia leads to serious impact in the patient’s functional and social life and to a great burden for their family members. Clozapine is the antipsychotic of choice for TR patients and it is associated with a greater reduction in psychotic symptoms and compliance when compared to other atypical antipsychotics in patients not responsive to prior antipsychotic trials. Centros de Atenção Psicossocial (CAPS), Psychosocial Care Centers, are community based mental health services, held by Brazilian Unified Health System (SUS), for the treatment of people who suffer from severe mental disorders. Since the beginning of the 2000’s, the CAPS have been the SUS main strategy for health care delivery to out-patients with schizophrenia and related disorders. This study aimed to identify the total number of TR patients with schizophrenia or related disorders in the CAPS of the city of São Paulo. Methods: A retrospective study was run in six CAPS of São Paulo. We started by selecting, through a first chart review in each center, all the cases where a diagnostic of schizophrenia or other psychosis (ICD F20 to F29) were recorded. Then, a screening questionnaire was given to the psychiatrists of each center so they identify possible cases of treatment failure among their patients. Psychiatrist had to confirm the diagnosis of schizophrenia or related disorder for all the patients and to establish the status of their clinical condition, by scores of the Clinical Global Impression – Severity Scale (CGI-S). Patients rated with a level of severity of moderately ill or above (= 4), non-clozapine user, were considered poor responders. The confirmation of resistance to treatment was made after a second and more extensive clinical chart review, when we pursued to identify the totality of antipsychotics that poor responders had ever received. Our criteria for identifying treatment resistance were based on the International Psychopharmacology Algorithm Project (IPAP) algorithm. Results: Research has been finished in four services. From a population of 1.790 patients, 430 with diagnoses ranging from F20 to F29 were identified. One hundred twenty-eight patients (CGI-S = 4) had their charts reviewed. We found that 77 of these patients (17.9%) met criteria for treatment-resistance, characterized by a level of moderate to severe symptoms, according to CGI-S, after the use of two different antipsychotics for adequate time and doses. The TR patients had taken a mean of 3.76 (SD = 1.331) antipsychotics. There were 21 patients taking clozapine (4.8%) among the 430 patients that entered this analysis. By the time of the Congress, results from other centers will be available. Discussion: These results show a low rate of TR recognition and low use of clozapine in the CAPS of São Paulo. This situation must be even worse in areas of the country with less economic development. Continued medical educational programs are necessary to empower clinicians to promptly recognize TR schizophrenia and to best manage clozapine.

A preliminary controlled trial of cognitive behavioral therapy in clozapine resistent schizophrenia

Eliza P. Barretto1, Monica Kaio1, Belquiz S. Avrichir1, Antonio A. Sa1, Maria G. Camargo1, Isabel C. Napolitano1, Fabiano G. Nery1, Jose A. Pinto1, Silvia Bannwart1, Silvia Scemes1, Elizangela Di Sarno1, Helio Elkis1

1Instituto de Psiquiatria da Universidade de São Paulo, São Paulo, SP, Brasil


Background
: Up to 40% of patients continue to experience psychotic symptoms in spite of taking antipsychotics in adequate dosage. For those treatment resistant patients, clozapine is the drug of choice, due to its superiority over conventional and atypical antipsychotics. However 30-40% of patients taking clozapine do not have a complete response to this drug (super-refractory patients). Cognitive Behavior Therapy (CBT) in combination with antipsychotic therapy has proven efficacy for resistant psychotic symptoms. We aimed to assess the efficacy of CBT in a homogenous population of super-refractory patients, in comparison with a “befriending” (BF) control group1. Methods: Outpatients with diagnosis of schizophrenia, with treatment-resistance according to Kane et al. criteria
2 were assessed for eligibility criteria. To be eligible, patients should be taking clozapine for at least 6 months without improvement of the psychotic symptoms, as defined by the presence of at least one psychotic symptom of  the BPRS-A “psychotic” subscale (hallucinations, delusions or suspiciousness) with  severity = 4. Therapists (either psychiatrists or psychologists) with a training in CBT participated in the study and applied CBT techniques for psychosis  or a nonspecific psychosocial approach (BF), which was designed to provide the same amount of contact with therapist as the CBT groups, with the same number of sessions at the same frequency. Results: Both groups had similar demographic characteristics at baseline, except for the age of onset of the disease, which was lower at BF group. Twelve subjects were allocated to CBT and 10 to BF. Twenty-one patients completed the trial; 22 patients completed the 21-week trial. A comparison of the outcome variables between groups was performed using the non-parametric repeated measures of analysis of variance. In comparison with the control group, the CBT group showed a significant improvement in the PANSS general psychopathology subscale (p = 0.025). Both groups showed improvement in positive symptoms throughout the trial, but only CBT group had an improvement that persisted at 6-month follow-up assessment. Discussion: Both groups had similar demographic characteristics at baseline, except for the age of onset of the disease, which was lower at BF group. Twelve subjects were allocated to CBT and 10 to BF. Twenty-one patients completed the trial; 22 patients completed the 21-week trial. A comparison of the outcome variables between groups was performed using the non-parametric repeated measures of analysis of variance. In comparison with the control group, the CBT group showed a significant improvement in the PANSS general psychopathology subscale (p = 0.025). Both groups showed improvement in positive symptoms throughout the trial, but only CBT group had an improvement that persisted at 6-month follow-up assessment.

Stigmatizing beliefs and attitudes of mental health professionals towards people with schizophrenia

Eduardo A. Leiderman1,2, Fernanda Ceresa1, Ivana Druetta1,2

1Proyecto Suma, Buenos Aires, Argentina/2Facultad de Ciencias Sociales, Universidad de Palermo, Buenos Aires, Argentina

Background
: Stigma is one of the most important barriers to rehabilitation in people suffering schizophrenia. Social distance and stigmatizing beliefs of mental health workers are more dangerous because they are less easy to avoid and can directly influence the outcome of patients and affect their recovery. Furthermore, mental health workers should be at the head of the fight to reduce discrimination towards the mentally ill. Our objective was to determine beliefs, attitudes and social distance of mental health workers towards people with schizophrenia.
Methods: We carried out a survey among mental health workers of Argentina during two national psychiatric conferences held in April and May 2010. A non-probability sample of 517 respondents was selected using convenience sampling. Their attitudes and social distance toward people with schizophrenia were assessed with several questions. Results: Mean age of respondents was 39,5 ± 11, 8 years old with a mean of 13, 5 ± 11,3 years of experience. Almost 60% of the surveyed were psychiatrists. Nine percent had a relative with schizophrenia. Although 94% believed that they have the right to know their diagnosis only 64% informed this diagnosis to the majority of their patients. Psychiatrists and male professionals were more likely to inform the diagnosis of schizophrenia to the patients than psychologists. Eighteen percent thought that the voting right of people with schizophrenia should be revoked, 34% believed that they should not obtain or renew the driver license and 13% thought that this group should not have children. Only 10% believed that people with schizophrenia can recover completely. Almost 6% thought that the only help that can be given consists in symptom treatment. Social distance was higher, particularly on intimate items as marrying with a person with schizophrenia or letting people with schizophrenia take care of children. Almost 18% would not recommend a person with schizophrenia for a job. Social distance was significantly greater in women, mental health workers with less than 15 years of experience and in those who treat a lower number of patients with schizophrenia. Discussion: There still exist a high social distance and stigmatizing attitudes toward people with schizophrenia among mental health workers. Personal contact with patients greatly contributes to the reduction of stigma. Anti-stigma campaigns should be directed towards mental health workers and should focus in reinforcing the awareness of human rights of the mentally ill and in decreasing the pessimistic view of the long-term outcome particularly during the first years of professional activity.


TREC-SAVE*: a randomised trial comparing mechanical testraints with use of seclusion for aggressive patients in psychiatric hospitals. Trial registration: ISRCTN 4945427 

Gisele Huf1, Evandro S. F. Coutinho2, Marco A. V. Ferreira3, Clive E. Adams4

1Instituto Nacional de Controle de Qualidade em Saúde, Fundação Oswaldo Cruz, Rio de Janeiro, RJ, Brasil/2Escola Nacional de Saúde Pública, Fundação Oswaldo Cruz, Rio de Janeiro, RJ, Brasil/3Instituto Philippe Pinel, Rio de Janeiro, RJ, Brasil/4Nottingham University, Nottingham, United Kingdom

Background
: The acronym is derived from the past studies undertaken by this team in Rio de Janeiro (Tranquilização Rápida-Ensaio Clínico [Translation: Rapid Tranquillisation-Clinical Trial]) combined with “Segurança no manejo da agressão: viabilidade e ética na contenção e isolamento” (Translation: Safe management of aggression: feasible and ethical study of seclusion or restraint). Thousands of people whose aggression is thought due to serious mental illness are secluded or restrained every day. Nevertheless, a Cochrane systematic review, such as other authoritative reviews, found no randomized controlled studies. Without fair testing these techniques will continue to be used outside of a rigorous evidence base. Methods: This was a pragmatic trial. Participants were anyone aggressive or violent in the emergency wards of a large psychiatric hospital in Rio de Janeiro (Psychiatric Institute Philippe Pinel) for whom restriction was felt to be indicated by nursing and medical staff, but also for whom they were unsure whether seclusion or restraint would be indicated. The use of strong cotton banding to edge of bed was compared to the use of a minimally furnished seclusion room with open but barred windows onto the nursing station. All participants used medication as prescribed. Main outcomes were time to restrictions lifted, and early change of treatment. Secondary outcomes were additional episodes, adverse effects/events, satisfaction with care during episode, discharge in 2 weeks. The Ethics Committee of Psychiatric Institute Philippe Pinel approved the study. Once this was a pioneer investigation, the aim of TREC-SAVE was to pilot methods, to generate data relevant for sample size calculations and, if possible, clinically useful data regarding treatment success. Data were analysed by intention-to-treat. Results: Recuitment started in 6th July 2010 and ended 24th Jan 2011, 105 participants were included. Groups of restraints (N = 51) and seclusion (N = 54) were similar regarding sex (female: 66,7% e 64,8%), age (mean [SD]: 40,8 [12,7] and 40,1 [14,9]) and cause of episode (psychosis: 82,4% e 77,8%), pointing to the success of the randomization procedures. By now, data are being analysed. Discussion: For the first time, a randomised pragmatic clinical trial was carried on to illustrate how objective evaluation of these techniques can, humanely and ethically, be applicable worldwide. This most coercive part of heath care has been neglected and has avoided any high-grade evaluation, despite concerning cheap and widely used techniques. This study could represent an important step on the use of these interventions.

Cardiovascular risk factors in patients with first-episode psychosis: a population-based study in São Paulo, Brazil

Isabela M. Benseñor1, Andre R. Brunoni1, Luiz A. Pilan1, Alessandra C. Goulart1, Geraldo F. Busatto1, Paulo A. Lotufo1, Marcia Scazufca1, Paulo R. Menezes1

1Universidade de São Paulo, São Paulo, SP, Brasil


Background
: Patients with psychosis are prone to develop cardiovascular diseases due to various factors including poor lifestyle habits and adverse effects of medications. This issue has not been sufficiently explored in low- and middle income countries. Our aim was to evaluate the cardiovascular profile of patients with first-episode psychosis in the city of São Paulo, Brazil.  
Methods: This is a cross-sectional ancillary study, which is part of a larger epidemiological community survey that assessed 200 first-episode psychosis in the city of São Paulo. We evaluated cardiovascular risk factors and lifestyle habits in a sample of patients from this study. Assessments were carried out through standard clinical examination and laboratory evaluation.
Results: Eighty-two patients (54% of the inception survey) agreed to participate. Mean age was 35 years and 54% were female. The following diagnoses were found in study participants: 20.7% were obese, 29.3% had hypertension, 39.0% dyslipidemia, 19.5% metabolic syndrome, and 1.2% had a 10-year risk of coronary heart disease based on Framingham Score greater than 20%. Regarding lifestyle habits, 72% were sedentary, 25.6% were current smokers, and 7.3% reported a heavy alcohol intake. Discussion: We confirmed a higher frequency of cardiovascular risk factors in this sample of first-episode psychosis patients compared to other psychiatric samples with the exception of smoking and alcohol intake. Dependence on family support could explain lower frequencies of smoking and alcohol intake. Frequencies of hypertension, diabetes, and metabolic syndrome were higher than that of a Brazilian healthy population of the same age. 

Oral Session 6 – Cognition and Psychopathology

Emotion processing and social cognition in patients with schizophrenia and unaffected first degree relatives

Salvador M. Guinjoan1

1FLENI, Department of Mental Health, University of Buenos Aires School of Medicine, Buenos Aires, Buenos Aires, Argentina

Background
: Schizophrenia is characterized by the presence of protracted prodromal symptoms, development of acute symptoms often in relation to a stressful situation, and loss of social abilities that are remarkably refractory to treatment and persist after acute manifestations have abated. This presentation describes the efforts of our group to define patterns of emotional response to stress, of brain activation during social cognitive tasks, and of performance in ecological tests of social functioning. Methods: Peripheral autonomic activity and functional MRI during stressful and social cognition tasks in patients with chronic schizophrenia, their first degree relatives, and healthy controls. Results: Patients with schizophrenia show an autonomic response to stress that persists beyond stimulus cessation, which is present also in their unaffected relatives but only in its parasympathetic aspects. Specific parasympathetic abnormalities are also present when siblings are presented with social cognitive tasks, which parallel performance deficits in this area. Unaffected siblings and patients share a failure to activate right-hemisphere brain structures such as middle and inferior frontal gyrus, superior temporal sulcus, temporoparietal junction, and precuneus, which are part of mirror neuron, mentalizing (theory of mind), and language brain circuits. Discussion: From these studies, we posit a series of related potential endophenotypes with explanatory pathophysiological value, namely parasympathetic dysfunction, mentalization deficits, and abnormal brain lateralization characterized by deficits of circuits of the right hemisphere pertaining to social cognition. The clinical implications of these findings are discussed, including opportunities for deficit remediation, along with potential future inquiries derived from our results, e.g., the relationships between brain activation during social tasks and specific social performance deficits.

Visual search impairments in schizophrenia

Elisa C. Dias1,2, Julianne Ammirati1, Filipe Braga1,3, Marina Ross1, Anna C. Nobre1,2, Daniel C. Javitt1,2

1Nathan Kline Institute for Psychiatric Research, Orangeburg, NY, United States/2New York University Langone Medical Center, New York, NY, United States/3Universidade Federal Fluminense, Niterói, RJ, Brasil/


Background
: Eye movements provide a direct measure of visual scanning of the environment and of selective attention. There is accumulating evidence that patients with schizophrenia (PSZ) have abnormal scanning patterns. The present studies examine patterns of eye movements, or scanpaths, of PSZ and healthy controls (HC) while subjects perform visual search in both naturalistic and artificial/controlled images. Naturalistic images have cognitive content, in addition to basic visual features, while controlled images do not, allowing the parametric variation of basic features such as contrast and crowding. In addition, controlled images allow examination of eye movements in two different types of search: parallel (efficient-EFS) and serial (inefficient-INS). In EFS, targets are salient and easily detected, and detection time is independent of number of distracters, or set size. In INS, targets, usually determined by a conjunction of features, are harder to find, and detection time increases with set size. INS requires the subject to scan the array in detail, requiring an organized search pattern, and is more dependent on dorsal stream/magnocellular visual pathways than EFS. PSZ have deficient magnocellular visual processing, so the expectation was that they would be particularly impaired in INS. Methods: In all tasks subjects were shown images and asked to search for a target while their eye movements were monitored by infrared tracking systems. In the first experiment (E1), subjects (PSZ, 27 and HC, 22) searched for an object (a key) hidden within 35 grayscale images of a busy naturalistic environments. In the second task (E2), subjects (PSZ, 13 and HC, 14) searched for a target among distracters in a controlled environment, consisting of sets of randomly distributed grey gabor patches (GP) of varying contrasts. For the EFS conditions, all stimuli had the same contrast, and the target GP had a different orientation. For the INS condition, half the stimuli had the same contrast as the target, but a different orientation, and the other half had the same orientation, but different contrast (background). Eight levels of contrast and five set sizes were used. Our main dependent measure was search time. We also analyzed saccade size and velocity, and fixation duration. Results: In all cases, PSZ took longer to find the targets than HC. They also had longer fixation times, and saccades were shorter and slower. In E1 PSZ had overall longer search times than HC, and in some cases, a very distinct and inefficient scanning pattern. In E2, although PSZ had an overall longer search time, in EFS the response pattern was similar to HC, i.e. increasing the set size did not alter the search time (no interaction of group and set size). For INS, however, there was an interaction of group and set size, and also of group and contrast levels. PSZ were particularly impaired when searching for low contrast stimuli or when the distracters had similar contrasts to the targets. Discussion: The present studies show that PSZ have abnormal search patterns which are not only dependent on the cognitive content of images, but also on the basic visual characteristics of the image. This suggests that the deficits in the magnocellular visual system found in PSZ may affect how patients scan their environment. Analyses of the patterns of eye movements in these visual search tasks contribute to the understanding cognitive impairments of PSZ, could help develop scanpath analysis as a biomarker for schizophrenia, and also may lead to the development of behavioral/cognitive therapies. 


UFD1L variants and cognitive performance


Vanessa K. Ota1,2, Arthur A. Berberian2,3,4, Ary Gadelha2,3,4, Fernanda T. Bellucco1, Denise M. Christofolini1, Marcos L. Santoro1,2, Vinicius C. Mrad1,2, Letícia M. N. Spíndola1,2, Airton F. Santos Filho2,3,4, Jair J. Mari4, Maria I. Melaragno1, Rodrigo A. Bressan2,3,4, Sintia I. Belangero1,2, Marilia A. C. Smith1


1Divisão de Genética, São Paulo, SP, Brasil/2Laboratório Interdisciplinar de Neurociências Clínicas (LiNC), Universidade Federal de São Paulo, São Paulo, SP, Brasil/3Programa de Esquizofrenia (Proesq), Universidade Federal de São Paulo, São Paulo, SP, Brasil/4Departamento de Psiquiatria, São Paulo, SP, Brasil

Background
: Schizophrenia is a complex and heterogeneous disease with a worldwide prevalence of 0.3 – 1.6%. Genetic and environmental factors interact to develop the disease. One known genetic risk for this disease is the 22q11.2 deletion, where UFD1L gene is located. UFD1L gene encodes a protein that seems to be involved in the neurodevelopment process and its rs1547931 and rs5746744 polymorphisms were associated with schizophrenia in a Chinese population. The aim of this study was to evaluate the association of UFD1L rs1547931 (G/C) and rs5746744 (G/C) polymorphisms with schizophrenia and cognitive performance in Brazilian population. Methods: A total of 180 patients with schizophrenia and 199 healthy controls were recruited from the PROESQ (Programa de Esquizofrenia) and LiNC (Laboratório Interdisciplinar de Neurociências Clínicas) of Unifesp. Each individual was assessed and diagnosed according to DSM-IV and genotyped for rs1547931 and rs5746744 by RFLP. One-hundred and nine patients with schizophrenia have undergone neuropsychological tests, which included Wisconsin Card Sorting Test, Hopkins Verbal Learning Test (HVLT) and Keep Track Task. Association of these polymorphisms with schizophrenia was verified by logistic regression analysis, using sex as a covariable. For the neuropsychological tests, schizophrenia patients were divided into two groups, considering both rs1547931 and rs5746744: C-allele carriers, which included both CC and GC genotypes, and GG-genotype carriers. Then, neuropsychological measures were submitted to analysis of covariance (ANCOVA), with sex, age and intelligence quotient as covariables. Results: Genotype frequency distribution of both rs1547931 and rs5746744 polymorphisms did not deviate from Hardy-Weinberg equilibrium. No association between each genotype and schizophrenia was found (rs1547931: p = 0.696; rs5746744: p = 0.618). Regarding both polymorphisms, GG-genotype carriers had lower performances in the verbal learning and evocation measures of the HVLT and updating, evaluated by Keep Track Task (p < 0.05). Discussion: GG-genotype carriers presented lower cognitive performances than C-allele carriers, though our results have shown no association of rs1547931 and rs5746744 with schizophrenia. Only one study has investigated these polymorphisms previously, reporting an association between G allele and schizophrenia in Chinese population. These preliminary data suggest that C allele of both polymorphisms may protect against lower performance on verbal learning, evocation memory and updating, which may be related to schizophrenia. These variables are also being measured in healthy controls to confirm the effect of this polymorphism. Other UFD1L polymorphisms were associated to schizophrenia and our previous study has shown an association to age at onset of the disease, confirming that this gene may play an important role in the pathophysiology of schizophrenia. Financial support: FAPESP; CNPq; CAPES, Brazil.

BDNF Val66Met polymorphism, cognition and clinical symptomatology in a Brazilian population-based sample of individuals with first-episode psychosis

Eduardo Martinho Jr1, Leandro Michelon1, Adriana M. Ayres1, Marcia Scazufca2, Paulo R. Menezes2, Robin M. Murray3, Teresa Rushe4, Homero Vallada1, Geraldo F. Busatto1


1Departamento de Psiquiatria, Faculdade de Medicina da Universidade de São Paulo, São Paulo, SP, Brasil/2Departamento de Medicina Preventiva, Faculdade de Medicina da Universidade de São Paulo, São Paulo, SP, Brasil/3Department of Psychosis Studies, Institute of Psychiatry, King’s College London, London, United Kingdom/4Department of Psychology, University of Manchester, Manchester, United Kingdom

Background
: Since BDNF expression seems to modify the pathogenesis of schizophrenia and mood disorders, we have decided to investigate the influence of the BDNF Val66Met polymorphism on cognitive performance and clinical symptomatogy in a population-based sample of patients presenting a first episode of psychosis (FEP). Methods: In a circumscribed area of São Paulo, 130 FEP patients (77 with schizophreniform psychosis and 53 with affective psychoses) and 191 healthy controls underwent BDNF genotyping. Additionally, they were assessed with the Structured Interview for DSM-IV, the Positive and Negative Syndrome Scale (PANSS), the Alcohol Use Disorders Identification Test, the South Westminster Questionnaire, and Annett’s handedness questionnaire. A short neuropsychological battery was applied both to FEP patients and controls including the forward and backward digit span tests from the Wechsler Memory Scale, and the Controlled Oral Word Association Test to measure verbal fluency.
Results: Genotype distributions had no deviation from Hardy Weinberg equilibrium in either of the two groups. There was no significant difference in the frequency of BDNF alleles between FEP patients and controls, or between the different subtypes of psychosis (schizophreniform versus affective psychoses). No interaction was found between genotypes and age, handedness, alcohol abuse, drug abuse, schooling, mean age of disease onset, use of benzodiazepines or use of antipsychotics either for the whole group or when the healthy controls and patients were examined separately, except for a higher presence of Met carriers among healthy women. Separate analyses stratified by gender demonstrated no significance influence of this parameter on cognitive and clinical assessment in any group. There were significant differences on schooling, and in the prevalence alcohol and drug abuse between FEP and controls subjects, but no significant differences were seen in regard to sex, age and handedness. No genotype x diagnosis interaction was found on cognitive performance. When comparisons were performed using the separate categories for schizophreniform and affective psychoses, there were again no significant differences for the three cognitive tests between the subgroups divided according to the Val66Met genotype. FEP patients who had the Met allele showed reduced negative symptomatology (p < 0.01). The subgroup analyses conducted using the separate categories for schizophreniform and affective psychoses indicated that such difference was evident for the mood disorder subgroup but not for the schizophreniform psychosis subgroup. Discussion: As in previous studies using similar methods, we have demonstrated a lack of association of the BDNF Val66Met polymorphism with psychosis, both of affective and non-affective nature. A decreased severity of negative symptoms was detected in affective FEP subjects that carried a Met allele, where negative symptoms are not stable over time, and do not persist during the post-acute phase of an affective psychosis. Our findings suggest that the BDNF gene Val66Met polymorphism does not have a pervasive influence on cognitive functioning and clinical symptomatology in FEP. Further longitudinal studies of FEP involving serial evaluations of clinical symptoms and cognitive performance are warranted, as well as studies using probes to evaluate the interplay between BDNF expression and dopaminergic transmission.

Increased serum levels of d-serine correlate with cognitive gains induced by neuroplasticity-based cognitive training in schizophrenia

Rogerio Panizzutti1,2, Melissa Fisher2,3, Coleman Garrett2,3, Wai Hong Man2,3, Sophia Vinogradov2,3


1Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, Brasil/2Department of Psychiatry, School of Medicine, University of California, San Francisco, CA, United States/3San Francisco Department of Veterans Affairs Medical Center, San Francisco, CA, United States

Background
: In animals, successful performance of a cognitive task induces increased brain levels of the NMDA-receptor co-agonist D-serine, a molecular system that plays a key role in leaning-induced neuroplasticity and that may be hypoactive in schizophrenia.  In a prior study, we demonstrated that intensive neuroscience-guided cognitive training induces significant improvement in cognition in schizophrenia subjects, but the biological mechanisms associated with these changes are unknown. The objective of this study was to investigate whether training-induced gains in cognition were associated with increases in serum D-serine in outpatients with schizophrenia. Methods: Design: Subjects were drawn from two randomized controlled trials.
Setting: San Francisco Department of Veterans Affairs Medical Center, San Francisco, CA; Department of Psychiatry, School of Medicine, University of California, San Francisco, CA. Participants: Ninety participants with schizophrenia and 15 matched healthy controls drawn from two clinical trials of cognitive training. Main Outcome Measures: Serum D-serine, L-serine, and glycine from schizophrenia subjects before and after they performed 40-50 hours of either neuroplasticity-based cognitive training (N= 47) or a computer games control condition (N= 43); MATRICS-based neuropsychological test scores. Results: At study entry, the mean serum D-serine level was significantly lower in schizophrenia subjects vs. healthy subjects, while the glycine levels were significantly higher. There were no significant changes in these measures at a group level after the intervention. However, in the active training group, increased D-serine was significantly and positively correlated with improvements in verbal learning and memory, and in global cognition. No such associations were observed in the computer games control subjects, and no such associations were found for glycine. Discussion: D-serine may be involved in the neurophysiologic changes induced by cognitive training in schizophrenia. Pharmacologic strategies that target D-serine co-agonism of NMDA-receptor functioning should be investigated as a means of enhancing the behavioral effects of cognitive training.

Neurocomputational models as an exploratory environment for schizophrenia research

Eduardo Mizraji1, Andrés Pomi1, Juan C. Valle-Lisboa1

1Group of Cognitive Systems Modeling, Biophysical Section, Facultad de Ciencias, Universidad de la República, Montevideo, Uruguay

Background
: Schizophrenia is a pathological condition whose complex genetic, neurodevelopmental and neurochemical causes (or triggers) interact in a subtle way with familiar, educational and social factors. Untangling this complex web of factors is a clear goal of schizophrenia research. Methods: In this communication we suggest that neurocomputational models can become a suitable instrumental environment to explore the complex interactions involved in the genesis and evolution of schizophrenia. In order to illustrate this, we focus over some aspects of language processing and production. Results: We first show language processing models derived from those investigated by Hoffman and McGlashan, based on pathological alterations in neural connectivity and centered in the production of auditory hallucinations. These models illustrate (inside the limited framework of their methodology) that similar pseudo-individuals (in fact, numerical simulated cases), although submitted to the same insults, vary in whether they display pathological symptoms or not. For instance, only a low fraction of the total cases develops the numerical phenomena interpretable as hallucinations. This is due to the fact that different manners of coding the same linguistic information produce different levels of behavioral fragility. Coding variability can be interpreted as the result of different training histories or different ways to map external objects onto multidimensional neural representations. In these situations the models try to represent the complex interaction between intrinsic biological predispositions (the high risk condition) and environmental factors. The other aspect we consider with these neurocomputational models is language production. Assuming that language production is a particular class of target-oriented motor action, we can represent a highly simplified version of this activity using a small neural model that describes the trained access to objectives (a small navigation neural model). With this model we show that reaching a target in the presence of deteriorated connectivity also depends on the training strategy and on the codes. Discussion: In both types of models, a mathematical representation of inter-neuronal communication is required. Hence, neurotransmission and neuromodulation are implicit, and the exploration of the simulated effect of psychotropic drugs is one of the important potentialities of these models. In addition, the learning capacities of neural models open the possibility of analyzing and experimenting in silico with the effect of environmental influences on the illness onset, and the design of therapies capable of integrating drug treatments with social and psychotherapy treatments

Posters

LASSBio-579: a N-phenylpiperazine compound active on animal models related to schizophrenia positive symptoms

Camila B. Antonio1, Gilda Neves2, Thais E. T. Pompeu3, Andresa H. Betti1, Mariana A. Pranke1, Carlos A. M. Fraga4, Eliezer J. Barreiro4, Teresa D. Costa1, François Noël3, Stela M. K. Rates1

1Programa de Pós-Graduação em Ciências Farmacêuticas, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brasil/2Laboratório de Farmacologia Molecular, Instituto de Ciências Biomédicas, Centro de Ciências da Saúde, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, Brasil/3Laboratório de Farmacologia Bioquímica e Molecular, Instituto de Ciências Biomédicas, Centro de Ciências da Saúde, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, Brasil/4Laboratório de Avaliação e Síntese de Substâncias Bioativas, Faculdade de Farmácia, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, Brasil

Background
: Previous studies on N-phenylpiperazine derivatives by our group indicated that LASSBio-579, LASSBio-580 and LASSBio-581 are potential antipsychotic lead compounds. Methods: The present study strengthened the pharmacological evaluation of these compounds by means of binding assays and behavioral models related to schizophrenia positive symptoms and potential side effects. Results: LASSBio-579, LASSBio-580 and LASSBio-581 presented a moderate affinity for D2-like, D4, 5-HT1A and 5-HT2A receptors. LASSBio-579 showed the best binding profile (Ki: D2-like = 0.11 µ M, D4 = 0.13 µ M, 5-HT1A = 0.093 µ M, 5-HT2A = 2.3 µ M and 5-HT2C = 8.9 µ M) and was the only one that inhibited apomorphine-induced climbing (5 mg/kg p.o.) and apomorphine-induced hypothermia (15 mg/kg p.o.). Thus it was elected for further pharmacological characterization. LASSBio-579 (0.5 mg/kg p.o.) was effective in the ketamine-induced hyperlocomotion test, which is indicative of effectiveness in schizophrenia positive symptoms. It also induced a dose-related motor impairment, catalepsy and a mild sedative effect but at doses 3 to 120 times higher than those with antipsychotic-like effects. Moreover, LASSBio-579 (0.5 and 1 mg/kg p.o.) reversed the catalepsy induced by WAY 100,635, a selective 5-HT1A receptor antagonist, corroborating its action on both dopaminergic and serotonergic neurotransmission and pointing to the contribution of 5-HT1A receptor activation to its pharmacological profile. Discussion: Our results characterize LASSBio-579 as a multi-target ligand active in animal models related to schizophrenia positive symptoms. With respect to its mechanism of action, binding to D2-like and 5-HT1A receptors could, at least partially, underlie its in vivo pharmacological properties, since there is a trend to manage positive symptoms via D2-like receptor, characteristic considered essential for psychosis control, and to relieve extrapyramidal symptoms via 5-HT1A activation. Furthermore, increasing literature data support the hypothesis that compounds exhibiting combined 5-HT1A and D2 properties may be effective in treating a broader range of symptoms of schizophrenia.

Repeated forced swimming impairs object recognition task in rats: a valuable tool to model cognitive symptoms of schizophrenia?


Milene Borsoi1, Alice F. Viana1, Andressa Braga1, Camila B. Antonio1, Paula Lunardi1, Carlos A. S. Gonçalves1, Stela M. K. Rates1

1Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brasil

Background
: The negative and cognitive symptoms of schizophrenia (SCZ) are more difficult to characterize than the positive symptoms and some of them are unique in humans. But others lend themselves more readily to animal testing. The immobility development by animals exposed to the repeated forced swimming is considered by some authors a behavior analogous to negative symptoms of schizophrenia, as lack of initiative and apathy. Furthermore, after forced swimming, rats have learning prejudice in tasks involving spatial memory, which some authors understand as a cognitive impairment. The aim of this study was to investigate the effect of repeated forced swimming (RFS) on the object recognition test (OR) and the on S100B protein levels in frontal cortex and hippocampus. Methods: Wistar male adults rats (n = 20) were exposed to RFS sessions (10 min) during three consecutive days. Twenty four hours after the last swimming session they were evaluated in the OR (n = 10) and the imunocontent of S100B (n = 10) was measured in frontal cortex (FCx) and hippocampus (Hc). Controls (naïve animals; n = 20) were exposed to the same behavioral and neurochemical evaluations. The OR test comprised a habituation; a training session, where the animals were exposed to two identical objects (A+A); and a test session, performed 24h post-training, where one of the objects was replaced by a different one (A+B). During the habituation session, was also evaluated the locomotion. The immunocontent of S100B was measured by ELISA in homogenated structures. Results: ANOVA repeated measures revealed a progressive enhancement of immobility response throughout the days (F(2,29) = 14,613; day 1 vs. day 2: p = 0.017; day 1 vs. day 3: p < 0.001; day 2 vs. day 3: p = 0.013). In the OR test the animals exposed to RFS showed impairment in the memory evaluated 24h post-training (Wilcoxon test, p = 0.506; Object A observation index = 0.48 ± 0.2 and Object B = 0.51 ± 0.2) while naïve animals did not (Wilcoxon test, p = 0.012; Object A observation index = 0.32 ± 0.1 and Object B = 0.68 ± 0.1). Time spent observing the both objects during the training session did not differ from control group (Student t test, p = 0.197; control: 24.29 ± 11.41s; RFS: 35.18 ± 21.12s). The locomotion was not altered (Student t test, p = 0.114; number of crossings of control: 98.6 ± 16.2 and RFS: 132.1 ± 11.1). The RFS did not altered the S100 levels in either FCx or Hc (Student t test, p = 0.947; control: 0.116 ± 00.8 ng/mg protein and RFS: 0.115 ± 0.009 ng/mg protein in FCx; p = 0.251 ± 0.001 ng/mg protein; control: 0.120 ± 0.008 ng/mg protein and RFS: 0.103 ng/mg protein in Hc). Discussion: Recognition memory confers the ability to discriminate between novel and familiar entities and is known that these cognitive processes/domains are disrupted in SCZ. This symptom class of SCZ is frequently unexplored in animal models, probably it is more difficult to characterize. In our study, we demonstrated that repeated forced swimming impaired the performance in object recognition test. This is in agreement with some studies, which demonstrated that animals exposure to repeated swimming show impairment in tasks related to cognition, such Morris Water Maze and strengths the notion that enhanced immobility could be considered analogous to negative symptoms of schizophrenia, contradicting the opinion of some authors that consider the enhanced immobility a successful strategy for dealing with stress. Interestingly the S100 levels, a protein commonly associated with neuropsychiatric disorders, was not modified. Some studies have been showed similar results in stressed animals, demonstrating that the S100B levels can not be ever elevated in animals with cognitive impairment.

Positive and negative symptoms-like behaviors in spontaneously hypertensive rats (SHR) are improved by antipsychotics: reinforcing this strain as a model of schizophrenia

Mariana B. Calzavara1,2, Raquel Levin1,2, Wladimir A. Medrano1, Valéria Almeida1,2, Roberto Frussa-Filho1, Vanessa C. Abílio1,2


1Universidade Federal de São Paulo, Departamento de Farmacologia, São Paulo, SP, Brasil/2Universidade Federal de São Paulo, LINC, Departamento de Psiquiatria, São Paulo, SP, Brasil

Background
: We have recently reported that spontaneously hypertensive rats (SHR) present a contextual fear conditioning deficit that is specifically reverted by antipsychotics and potentiated by psychostimulants and other proschizophrenia manipulations. Based on these findings, we proposed that this deficit could be used as a model to study emotional processing impairment observed in schizophrenia. In addition, this strain is suggested as a model of ADHD (attention deficit/hyperactivity disorder). Considering that schizophrenia and ADHD are also characterized by poor social function, this study aimed to investigate possible behavioral deficits of SHR in a social context: social interaction and hyperlocomotion (that mimics negative and positive symptoms of schizophrenia, respectively, and could be related to the behavioral alterations associated to ADHD) in SHR and Wistar rats. Furthermore, we sought to examine the effects of typical and atypical antipsychotics (used for the treatment of schizophrenia) and a psychostimulant (used to treat ADHD) on these behaviors. Methods: Pairs of unfamiliar rats were treated with vehicle, 0.1 mg/kg haloperidol, 5 mg/kg quetiapine or 5 mg/kg clozapine. The animals were placed in an open-field for 10 minutes and social behaviors and locomotion were scored. Results: The results show that the SHR group exhibit a poor social performance that is specifically ameliorated by atypical antipsychotics. In addition, the SHR group displayed hyperlocomotion that was attenuated by all antipsychotics and enhanced by amphetamine. Discussion: Our results indicate that SHR exhibit a behavioral and pharmacological profile that meets important validity criteria for use as a model of the negative and positive symptoms of schizophrenia.

Effects of repeated treatment with haloperidol on information processing deficits presented by SHR (spontaneously hypertensive rats)

Mariana B. Calzavara1,2, Lizia Ferreira1,2, Camila M. Santos1,2, Raquel Levin1,2, Tânia Libânio1,2, Rodrigo A. Bressan2, Vanessa C. Abílio1,2

1Universidade Federal de São Paulo, Departamento de Farmacologia, São Paulo, SP, Brasil/2Universidade Federal de São Paulo, LINC, Departamento de Psiquiatria, São Paulo, SP, Brasil

Background
: We have described that spontaneously hypertensive rats (SHR) present deficits in contextual fear conditioning (CFC) and in an operational measure of sensorimotor gating - the prepulse inhibition of startle (PPI) - that is specifically reverted by antipsychotics and potentiated by proschizophrenic manipulations. In this sense, we suggested that these deficits could be a useful animal model to study abnormalities in information processing in schizophrenia. In those experiments, the beneficial effects of antipsychotics were seen after an acute treatment. The aim of the present study was to investigate the effects of a repeated pretreatment with haloperidol (typical antipsychotic) on the PPI and on the CFC deficits presented by SHR. Methods: Adult male Wistar rats (WR) and SHR (n = 10) were treated with vehicle or 0.5 mg/kg haloperidol during 17 days. On the 12th day, the rats were submitted to the CFC training session. In this session, they were individually placed in a dark chamber with a grid floor. After 150 sec, 0.4 mA foot shocks lasting 5 sec were applied every 30 sec for the subsequent 150 sec. Thirty seconds after the last foot shock, the animal was removed from the apparatus. The contextual conditioning test was performed twenty-four hours after the training: each animal was placed in the same dark chamber, without receiving foot shocks. The freezing duration (defined as complete immobility of the animal, with the absence of vibrissae movements and sniffing) was quantified during 5 min. On the 17th day, the rats were submitted to the PPI test that began by placing a subject in the stabilimeter cage where the animal was exposed to the background noise for 5 min. After this acclimatization period, the rats were presented with a series of 10 stimuli (pulse alone - 120 dB, 50ms duration), with an inter-trial interval of 20s. Thereafter, the PPI modulation of the acoustic startle was tested. This phase consisted of 60 trials pseudorandomly divided into four different categories presented with an inter-trial interval of 20 s: 20 presentations of pulse alone (120 dB, 50ms duration), 10 presentations of prepulse alone (75 dB, 3000 Hz frequency, 20 ms duration), 20 presentation of prepulse + pulse (with 40 ms interval) and 10 no stimuli trials (stabilimeter recordings obtained when no stimulus was presented). The level of PPI in each rat was determined by expressing the prepulse + pulse startle amplitude as a percentage decrease from pulse-alone startle amplitude (%PPI = 100 - [100 x (PP/P)]). All the behavioral manipulations were performed before the daily injection of the respective treatment. Results: Repeated pretreatment with haloperidol did not improve the deficit in CFC but ameliorated the PPI deficit presented by SHR. Discussion: SHR presented deficits in CFC and PPI, as we have previously reported. Contrary to the acute treatment, the repeated pretreatment with haloperidol did not revert the deficit on the CFC. Conversely, the repeated pretreatment with haloperidol improved de deficit in PPI (as seen for the acute treatment).


Risperidone-induced antidyskinetic effects on an animal model of tardive dyskinesia: influence of aging

Rita de C. Carvalho1, Sonia R. Kameda1, André T. Coleman1, Luciana T. R. Carvalho1, Rosana de A. Ribeiro1, Roberto F. Filho1

1Universidade Federal de São Paulo, São Paulo, SP, Brasil

Background: Tardive dyskinesia (TD) is the principal adverse effect of long-term treatment with classical neuroleptics and has been related to the development of nigrostriatal dopaminergic supersensitivity (NDS). Evidence from clinical studies show that atypical neuroleptics produce a lower incidence of DT in adult patients. However, the effects on aged people remain overlooked. The aim of the present study was to verify the development of orofacial dyskinesia (OD) and NDS in young adult or aged mice after long-term treatment with the typical neuroleptic haloperidol (hal) concomitantly or not with the atypical neuroleptic risperidone (ris). : Three-month-old or twenty-three-month-old male mice were randomly assigned to one of the following groups: veh-veh, ris-veh, veh-hal or ris-hal. Animals were concomitantly treated intraperitoneally for 20 days with vehicle (veh) or 2 mg/kg haloperidol (hal) or 2 mg/kg of risperidone (ris). The quantifications of orofacial dyskinesia (number of vacuous chewing movements during a 10-minute session) as well as NDS (evaluated by apomorphine-induced stereotyped behavior) were performed 24 h after the last injection. Results: Both adult and aged animals treated with haloperidol presented increased OD and stereotyped behavior when compared to the control group. The treatment with risperidone per se did not promote an increase in OD or in the stereotyped behavior in both ages. Concomitant treatment with risperidone reversed the development OD and the increase in stereotyped behavior induced by haloperidol in adult and aged mice. Still, aging potentiated haloperidol-induced OD. Discussion: The long-term treatment with the atypical neuroleptic agent risperidone per se did not induce the development orofacial dyskinesia and also reversed haloperidol-induced OD in both adult and old mice. These effects seem to be related to NDS. Apoio financeiro: CAPES, CNPq, AFIP e FAPESP.

Searching for neuregulin-related ncRNA: a comparative in silico analysis

Alexandre R. Paschoal1, Alvaro M. Dias2

1Instituto Tecnológico da Universidade Federal do Paraná, Londrina, PR, Brasil/2Faculdade de Medicina da Universidade de São Paulo, São Paulo, SP, Brasil

Background: Recent advances in genetic neuroscience shed increasing light in the role of protein interactions in schizophrenia’s endophenotype. In this context, considerable attention has been driven to protein landscapes that regulate neuron survival and efficient nerve conduction, in relation to which the NRG1-ErbB4 interaction has been argued to play a prominent role. Bearing that in mind, it is important to consider that much less is known about the role of Non-coding RNAs (which are transcribed but do not code proteins), within the landscape of such essential components of schizophrenia’s endophenotype. Such picture contrasts with cancer studies, in relation to which the diversity of these RNAs (also known as ncRNAs) has been linked to tumor formation and progression. Indexed experimental studies in molecular psychiatry and available databases that include related reports on ncRNAs (SZGR database, microRNA.org, NRED, etc.) seem to lack the comprehensive demands of the field. Based upon the plethora of reported roles of ncRNAs in other medical conditions were cell grow also occupy a prominent role (e.g., cancer research), it is sensible to consider that there may be a gap between the aforementioned psychiatric reports and the actual diversity, type and function of ncRNAs involved in neuregulin interactions. Objective. This study aims to define neuregulin-related ncRNAs, so as to advance knowledge about schizophrenia’s endophenotype. : The first step of this study was to make in silico analysis, based on comparative genomics of human NRG1 gene and homologous forms in different species, so as to advance evolutionary time-scales of different types of neuregulin-related ncRNAs. Our main strategy at this stage was to include data taken from both Old World and New World primates, mice and humans. This strategy not only provided us with findings regarding phylogenetic conserved ncRNA, but also with the potential to consider human ncRNAs in regard to the evolutionary time-scale. After all that was done, we began a much more complex task: the annotation of this candidates. Such goal depends on the ability to properly deal with the diversity, variability in types, shape and size of the ncRNAs. Different from proteins, ncRNAs lack evident markers (such as domains regions) that aid traditional annotation processes. Moreover, compensatory changes in the base-pairs preserve the secondary structure but not necessarily the primary sequence. It is not suitable to rely exclusively on similarity search, in order to achieve proper ncRNA annotation. Results: Hence, a pipeline with several different modules was developed and used herein; and the task as whole achieved its end with in silico inference of such pipeline results. Discussion: Taking for granted that neuregulins were several times reported as involved in consolidation of schizophrenia’s endophenotype, this study can be assumed to contribute to the field as it represents a first step toward the possibility of understanding the role of ncRNAs in neuregulin-related processes.

Prevention of ketamine-induced hyperlocomotion in mice by the essential oil of Alpinia zerumbet leaves

Fernanda Y. R. de Araújo1, Gersilene V. de Oliveira1, Patrícia X. L. Gomes1, Francisca C. F. de Sousa1, Andre F. Carvalho1, Silvãnia M. M. Vasconcelos1, Danielle S. Macêdo1, Nathalia L. Nascimento1


1Departamentos de Fisiologia e Farmacologia, Universidade Federal do Ceará, Fortaleza, CE, Brasil

Background: Alpinia zerumbet (Pers.), from zingiberaceae family is popularly known in Brazil by “colônia” being used in folk medicine as diuretic, analgesic and anxiolytic. Recent paper from our research group showed a possible antipsychotic effect of the essential oil from Alpinia zerumbet leaves against apomorphine-induced stereotypies, a pharmacological model of schizophrenia positive symptoms. Objectives: Assess the antipsychotic effect of Essential oil from Alpinia zerumbet leaves (EOAZ) using the ketamine-induced hyperlocomotion as a pharmacological animal model of schizophrenia, also evaluating the in vitro antioxidant effects of the oil in the brain. : ketamine-induced hyperlocomotion behavior was assessed in Swiss mice (n = 7-9) pretreated with EOAZ (50, 100 mg/kg, i.p.) or vehicle 30 min before ketamine (ket- 20 mg/kg, i.p.). Immediately after ket administration the animals were submitted to open field test. Haloperidol (Hal – 0.2 mg/kg, i.p.) was used as standard antipsychotic. In vitro oxidative stress determination was performed in whole brain homogenates without cerebellum in the presence of EOAZ (25, 50, 100 mg/ml) or tocoferol (vit E 100 mg/ml – as standard antioxidant). After 1 h incubation of previously frozen (-20°C for 24 h) brain homogenate at 37°C, the antioxidant activity was calculated for each concentration of the oil. The samples submitted to oxidative stress (i.e. frozen and thawed at 37°C) were used as positive controls (PC). The samples frozen and not incubated for 1 h at 37°C were used as negative controls (NC). The same homogenates were used to assess the in vitro effects of the EOAZ on nitric oxide (NO) production assessed by determination of nitrite levels, lipid peroxidation (MDA levels) and reduced glutathione (GSH) to evaluate defenses against oxidative stress. For statistical analyses ANOVA followed by Student-Newman-Keuls were performed considering P < 0.05. The study was approved by the University Animal Ethics Committee (protocol no. 45/10). Results: Ket treatment increased by 181% the number of crossings in the open field test as compared to control animals. Pretreatment with EOAZ 100 mg/kg and HAL significantly decrease ket-induced hyperlocomotion as compared to ket (Control: 85 ± 22.9; ket: 191 ± 62; EOAZ 50 + ket: 219.5 ± 97.9; EOAZ 100 + ket: 129 ± 29; HAL: 51 ± 11.1; HAL + ket: 7.5 ± 2.9). In vitro experiments showed that positive controls presented a 83% increase in MDA levels, decrease in nitrite content and GSH levels as compared to negative controls. The EOAZ in all concentrations studied 25, 50 e 100 µg/ml) reduced lipid peroxidation as compared to positive control, an effect comparable to the one seen in Vit E group. In relation to GSH there was an increase in this antioxidant defense with EOAZ in the concentrations of 50 and 100 µg/ml. Nitrite level was restored by the use of EOAZ and vit E (Lipid peroxidation − NC: 128 ± 58.1; PC: 585.5 ± 34.9; EOAZ 25: 81.7 ± 16.1; EOAZ 50: 195 ± 46.8; EOAZ 100: 141.3 ± 24.8; VIT E: 94.2 ± 67.2; GSH levels- NC 2267 ± 271.2; PC: 1515 ± 216.7; EOAZ 25: 2490 ± 225.5; EOAZ 50: 3061 ± 460.9; OEAZ 100: 3487 ± 362.9; Vit E: 3966 ± 496.8; Nitrite content- NC 12773 ± 175.2; PC: 10373 ± 1084; EOAZ 25: 11542 ± 1291; EOAZ 50: 14065 ± 532.9; OEAZ 100: 13966 ± 542; Vit E: 14829 ± 1382). Discussion: The results showed that the EOAZ was able in the prevention of ketamine-induced hyperlocomotion, presenting, therefore, antipsychotic effect. The same oil prevented in vitro oxidative stress generation, what may be involved in its antipsychotic mechanism of action.

Behavioral and biochemical evaluation of animals chronically exposed to cigarette smoke during the prenatal period: implications in the development of schizophrenia

Pedro F. Deroza1, Daiane B. Fraga1, Renata D. de Luca1, Fernando V. Ghedim1, Isabelle M. Miranda1, Alexandre Silverio1, Andresa Cipriano1, João L. Quevedo1, Ricardo A. Pinho, Renan P. Souza1, Alexandra I. Zugno1

1Universidade do Extremo Sul Catarinense, Criciúma, SC, Brasil

Background: Schizophrenia is a heterogeneous disease and extremely debilitating that can be caused by two factors: heredity and environmental influences. Studies show that changes in the enzyme acetylcholinesterase (AChE) in the prenatal period are associated with deficits in neuronal development of serotonin and dopamine which can result in long-term behavioral abnormalities. The aim of our study was to evaluate behavioral and biochemical parameters in adult rats chronically exposed to cigarette smoke during the prenatal period. : Wistar female rats were exposed to 12 cigarettes per day throughout pregnancy. We evaluated the activity of AChE and locomotor activity of adult male rats of this offspring, submitted to animal model of schizophrenia induced by acute doses of ketamine (5 mg/kg, 15 mg/kg and 25 mg/kg). The activity of AChE was determined by the method of Ellman et al. (1961). The locomotor activity was assessed in the open field. Results: We observed that administration of acute doses of ketamine significantly increased the AChE enzyme activity in all structures studied (PFC, amygdala, striatum and serum) in both groups: rats exposed and not exposed to cigarette smoke during prenatal period compared with those receiving only saline. The results also showed that locomotor activity increased significantly in the group given acute dose of 25 mg/kg of ketamine and were not exposed to cigarette smoke and the doses of 5 mg/kg, 15 mg/kg and 25 mg/kg groups who were exposed to cigarette smoke compared with the control group. Discussion: Exposure to cigarette smoke in the prenatal period causes changes in the activity of AChE, behavioral changes in adulthood and may contribute to the development of schizophrenia. Elegant studies appointed a possible interaction between the AChE enzyme and glutamatergic functions (Koutsoviti-Papadopoulou et al., 2005). In addition, Dong et al. (2004) indicated that AChE overexpression disrupts glutamatergic system and result in damage to synaptic structure and excitatory functions. In current study, an increase of the cholinesterases was observed with ketamine treatment in all doses tested in both PCSE control and PCSE rats.

Effect of long-term treatment with risperidone on prefrontal cortex gene expression in an animal model of schizophrenia: the spontaneously hypertensive rats (SHR)

Mariana C. Diana1,2, Marcos L. Santoro1,3, Camila M. Santos1, Vanessa K. Ota1,3, Vinícius C. Mrad1,3, Letícia M. N.
Spíndola1,3, Marilia A. C. Smith3, Vanessa C. Abílio1,2, Sintia I. N. Belangero1,3


1Laboratório Interdisciplinar de Neurociências Clínicas (LiNC), São Paulo, SP, Brasil/2Departamento de Farmacologia, Universidade Federal de São Paulo, SP, Brasil/3Divisão de Genética, Departamento de Morfologia e Genética, Universidade Federal de São Paulo, São Paulo, SP, Brasil
Background: Schizophrenia is a complex and severe mental illness that affect 0,3% to 1,6% of the general population. Genetic and environmental factors interact to develop the disease. The symptoms are characterized in positive - hallucinations and delusions, negative -" reduced expression of normal behaviors (reduced social interaction), and cognitive - reduced cognitive capabilities (impaired attention). Nowadays, most patients are treated with atypical antipsychotic drugs, which present fewer side effects. However, the variability of response to treatment is still a barrier. Recently, our group suggest that the SHR (Spontaneously Hypertensive Rat) strain - based on its behavioral, pharmacological and neurochemical profile - could be a useful animal model to study several aspects of schizophrenia. Thus, the aim of the present study was to compare the gene expression of neurotransmitters receptors and regulators in prefrontal cortex of SHR treated with risperidone or with control solution. : Adult male SHR were treated during one month with vehicle (n = 5) or with 0.5 mg/kg risperidone (n = 5). The animals were euthanized and the prefrontal cortex was dissected. Then the RNA was extracted and converted to cDNA, in order to perform the gene expression analysis using PCRarray technique, which verifies the expression of 84 genes related to neurotransmission plus five housekeeping genes simultaneously. We utilized the <a href=-http://sabioscience.com/pcr/arrayanalysis.php->Web-Based PCR Array Data Analysis software, which uses t-test to investigate the significance of each gene. It was considered relevant p-values less than 0.05 and fold regulation greater than 1.3. Results: 8 genes showed alteration in gene expression: Abat (-1.73 fold; p = 0.016), Ache (-1.74 fold; p = 0.016), Chrnb2 (-1.73 fold; p = 0.016), Gabra5 (-1.5 fold; p = 0.01), Glra3 (-1.51 fold; p = 0.009), Prokr2 (-1.32 fold; p = 0.026), Slc5a7 (-1.31 fold; p = 0.029), Sstr4 (-1.52 fold; p = 0.034). Discussion: The mechanism of action and the metabolization of the antipsychotic drugs in the nervous system have not been completely elucidated. These analyses strongly suggest that risperidone decreases the expression of these genes in prefrontal cortex. It is known that the GABAergic and cholinergic pathways are involved in the physiopathology of some neural disease. The underexpression of Abat and Ache, both involved in the neurotransmitter metabolization (GABA and Acetilcholine, respectively), could influence drug response or its degradation. Moreover, changes in the expression of these genes may be associated with the beneficial effects of antipsychotic treatment on the behavioral alterations presented by SHR. Future studies will be conducted by our group for further elucidations about the role of these genes in the physiopathology of schizophrenia, and the actions of other antipsychotic drugs in the genetic material.

Chronic exposure to cigarette smoke during gestation provokes changes in the mitochondrial respiratory chain of the offspring adult
rats: potential relevance to schizophrenia


Fernando V. Ghedim1, Daiane B. Fraga1, Ricardo F. Julião1, Renata D. de Luca1, Alexandre Silverio1, Andresa Cipriano1, Isabela C. Jeremias1, Gisele D. Bez1, Liz M. Mello-Santos1, Ricardo A. Pinho1, Emilio L. Streck1, Joao L. Quevedo1, Alexandra I. Zugno1

1Universidade do Extremo Sul Catarinense, Criciúma, SC, Brasil

Background: The schizophrenia is characterized by profound disturbances in mental functions, behavior and emotions. The appearance of the disorder usually occurs by the combination of genetic and environmental factors responsible by deficits in the neural connectivity and synchronization. The developing brain needs an increased metabolic demand. Thus, one mode of tissue adaptation to this energetic demand occurs via modulation of mitochondrial activities. : Pregnant female Wistar rats were exposed to 12 commercially filtered cigarettes per day, daily for a period of 28 days. We evaluated the respiratory chain enzyme activities in prefrontal cortex, hippocampus and striatum in male adult offspring rats, subjective to animal model of schizophrenia. Results: We observed in prefrontal cortex, hippocampus and striatum that the activities of the mitochondrial respiratory chain complexes I, II and II-III didn't differ statistically compared to control group. However, we verified that cigarette smoke (CS) in prenatal period resulted in a significant decrease in the enzymatic activity of the complex IV in striatum, in addition, the administration of acute doses, 5, 15 and 25 mg/kg of ketamine in CS group provoked a decrease in activity of the complex IV too, in comparison to control group. Discussion: We suggested that cellular damage provoked by CS (environmental insult) in gestation persists until adulthood and that the administration of ketamine combined with CS in the prenatal period can play a critical role in inducing deficits observed in schizophrenia. However, smoking in pregnancy provokes molecular events that are not yet completely known, hence, the continual integration of epidemiological and experimental work are need to understanding the cellular and molecular mechanisms involved in environmental insults suggested to account for some of the abnormal responses to behavioral stimuli reported in neuropsychiatric disorders.

Effect of a nitric oxide synthase inhibitor on startle reflex response and prepulse inhibition of spontaneous hypertensive rats (SHR)

Gabriela Tunes1, Nicole Henriques-Santos1, Michelle Brosco1, Vanessa Abilio2, Cristiane Salum1

1Universidade Federal do ABC, Centro de Matemática, Computação e Cognição, Santo André, SP, Brasil/2Universidade Federal de São Paulo, Departamento de Psiquiatria, São Paulo, SP, Brasil

Background: Information processing can be divided in two parts consisting on pre-attentional and attentional processing. Sensorimotor filter is involved on pre-attentional events in order to ensure an adequate information processing avoiding that a chaotic flow reaches consciousness. A deficit on this filter may lead to cognitive or psychiatric disorders like attentional deficit and hyperactivity disorder (ADHD) or schizophrenia. The prepulse inhibition (PPI) test is a model widely used to study schizophrenia, since it can detect deficiencies on information processing. PPI consists on a reduction of the startle response to a pulse when this stimuli is preceded by a low intensity prepulse stimuli. It has been shown that this effect is mediated by dopaminergic and glutamatergic neurotransmissions and recently nitric oxide (NO) has been demonstrated to modulate this neurotransmissions. Spontaneous hypertensive rats (SHR) have been extensively used as a model of ADHD and more recently as a possible model to study schizophrenia. The aim of the present study was to investigate the effect of a NO synthase (NOS) inhibitor on the startle reflex and PPI responses of SHR. : Thirty male Wistar rats and SHR received an injection i.p. of the NOS inhibitor, N-Nitro-L-arginine, L-NOARG, (40 mg/kg) or saline 1 h before the test. Each rat was tested with PPI protocol consisting on five minutes of acclimation (background noise of 57dB), followed by 10 presentations of pulse (white noise of 110 dB, 30s of interval, 40 ms) for habituation and then the PPI test itself consisting on pseudorandom presentations of 64 stimuli: pulse (P), pre-pulse (PP, pure tone, 3 kHz, 69, 73 and 81 dB, 20 ms), PP+P (100 ms between stimuli) and null (no stimuli). The level of PPI in each rat was determined by expressing the PP+P startle response (ASR) as a percentage (%PPI) decrease from pulse-alone ASR. Statistical analysis of %PPI and ASR were performed with repeated measures analysis of variance (ANOVAs) with stimulus intensity (69, 73, 81 dB) as within factor and treatment and strain as between factors. All procedures were previously approved by the Animal Care and Use Committee of Federal University of ABC. Results: ANOVA for the %PPI showed that there was not a significant effect of strain neither of treatment. ANOVA for the ASR to P and PP+P showed a significant main effect for strain but not for treatment. The post-hoc analysis with Duncan test showed that SHR presented significant lower ASR to P, PP(69)+P, PP(73)+P compared to Wistar rats. Additionally, there was a threshold effect of strain on ASR to the PP(81)+P which was on lower on SHR than on Wistar rats and also a threshold effect of L-NOARG on ASR to PP(69)+P. Discussion: In spite of our results having not detected a deficit on PPI of SHR rats, it was clear demonstrated a deficiency on information processing detected by ASR to the stimuli P and PP+P. There was only a slight effect of L-NOARG on the ASR to PP+P but this could not indicate a significant effect of this treatment. The present study suggests that the effects of NO on SHR should be further investigated with higher doses of NOS inhibitors or more specific neuronal NOS inhibitor.

Behavioral characterization of periadolescent SHR (spontaneously hypertensive rats): possible prodromal signs in an animal model of schizophrenia

Suzy T. Niigaki1,2, Lizia Ferreira2, Douglas A. Gouvêa1,2, Raquel Levin1,2, Valéria Almeida1,2, Tania C. Libânio2, Mayra A. Suiama1,2, Mariana B. Calzavara2, Vanessa C. Abílio1,2


1Departamento de Farmacologia, Universidade Federal de São Paulo, São Paulo, SP, Brasil/2Laboratório Interdisciplinar de Neurociências Clínicas, Universidade Federal de São Paulo, São Paulo, SP, Brasil

Background: The value of studying prodromal effects of schizophrenia rely on the attempt to prevent this disease. In this context, given that we recently proposed SHR as an animal model of schizophrenia, this study aims to characterize some behaviors related to schizophrenia in this strain during the periadolescence. : Young Wistar (W) and SHR (n = 20/strain) were evaluated in the social interaction (SI), contextual fear conditioning (CFC), tone fear conditioning (TFC) and latent inhibition (LI) tasks (between 25 and 40 post-natal days). For SI, pairs of unfamiliar rats were submitted to an open-field for 10 minutes, forming the groups: W-W, W-SHR, SHR-SHR, SHR-W, according to which strain they passed with. Active interaction (sniffing, following or grooming the pair), passive interaction (animals lie within a distance of 5 cm from each other) and locomotion (number of floor squares entered) were quantified. The LI procedure consisted in comparing freezing response of animals exposed (E) or not (NE) to the context and tone before the training session of the CFC/TFC task, forming the groups: W-NE, W-exposed W-E, SHR-NE and SHR-E. In the Training Session of CFC/TFC, rats were individually placed in a dark chamber for 5 minutes. After 150 seconds, 4 blocks of 5s-0.6mA shocks preceded by a 5-s tone were applied every 30s. Twenty-four hours later, Test Session of CFC was conducted for 5 minutes and freezing was quantified in this same chamber without the presentation of footshocks. Twenty-four hours later, test session for TFC was conducted and freezing was quantified in a different chamber after the tone presentations. Results: In the social interaction paradigm, SHR-SHR presented less passive interaction than W-W, while SHR-W presented more passive interaction than SHR-SHR. For active interaction, both SHR-SHR and SHR-W presented less active interaction than W-W and W-SHR. No differences between groups were found in the locomotion. In both CFC and TFC tasks, SHR-NE and SHR-E presented less freezing than W-NE and W-E. In addition, W-E presented less freezing than W-NE (revealing the LI only for this strain). Discussion: Periadolescent SHR, as seen previously in adulthood by our group, exhibit social interaction and emotional processing deficits (revealed by the deficits in fear conditioning) as well as an absence of latent inhibition. Accordingly, social withdrawal and cognitive deficits may be presented in a prodromal phase of schizophrenia. On the other hand, hyperlocomotion (that mimics psychosis) is absent in young SHR, in accordance with the course of schizophrenia that is marked by the manifestation of a first psychosis episode at adulthood.

Effect of epileptic seizures euring brain development on prepulse inhibition of the acoustic startle reflex in rats tested after puberty

Regina B. Silva1, Alexandre V. Silva1, Giovanna P. Labatte1

1Santos, São Paulo, Brasil

Background: Perinatal events may be related to the development of schizophrenia. Individuals with epilepsy are at increased risk of having psychotic symptoms that resemble those of schizophrenia. We investigated the effects of epileptic seizures during a postnatal vulnerable period of brain development on prepulse inhibition (PPI) of the acoustic startle reflex and locomotor activity in rodents tested on post puberal phase. PPI is an operational measure of sensoriomotor gating and is reduced in schizophrenia patients. : Male Wistar rats (250-280 g) were randomly divided into three groups: control (CTRL, n = 8), maternal separation (MS, n = 8) and pilocarpine (PILO, n = 6). For induction of status epilepticus, the pups were isolated from their dams and received intraperitoneal injections of pilocarpine hydrochloride 2% (380 mg/kg, Pilo, Merck) in postnatal days (PD) 7, 8 and 9. They were observed for five hours.<s> CTRL group passed by the same protocol except that they received intraperitoneal injections of saline solution, 0.9%. MS group was left undisturbed with their dam in the experimental room for the same period of time. This group was used to assess the effects associated with maternal separation. After puberty (PD 56), each animal was tested for PPI and locomotor activity. Results: Two-way ANOVA revealed significant differences among treatments [F(2,65) = 6.42, p < 0.003]. No difference was found between prepulse intensities [F(2,65) = 0.06, p = 0.93], and there was no interaction between treatment and prepulse intensity [F(4,65) = 0.41, p = 0.79]. Rats of the PILO group showed impaired PPI (Post hoc Tukey test, p = 0.003). There was no difference in the mean amplitude of the startle reflex among groups [F(2,21) = 0.76, p = 0.47]. Rats of the PILO group showed a significant decrease in locomotor activity expressed by the number of crossings in the open field test [F(2,21) = 4,01; p = 0.03]. Discussion: The results of this study showed a relevant association between prolonged neonatal seizures and deficits in sensoriomotor gating qualitatively similar to the disturbances seen in schizophrenic patients. As it has been suggest that schizophrenia may, in part, be a neurodevelopmental disorder these data suggest that the pilocarpine model may represent an interesting developmental manipulation for investigating the influence of early life events on the information processing and motor activity in adulthood.

Effects of a nitric oxide synthase inhibitor on deficits in prepulse inhibition caused by NMDA receptor antagonists

Nicole Henriques-Santos1, Michelle Brosco1, Gabriela Tunes1, Elaine Del-Bel2, Cristiane Salum1

1Universidade Federal do ABC, Centro de Matemática, Computação e Cognição, Santo André, SP, Brasil/2Universidade de São Paulo, Faculdade de Odontologia de Ribeirão Preto, MEF, Ribeirão Preto, SP, Brasil


Background: Considering the deficits in sensory-motor filter present in several disorders such as schizophrenia, one strategy to clarify the pathophysiology of this deficiency is to investigate the effects of pharmacological manipulations on prepulse inhibition (PPI) in animal models. It is known that the nitric oxide (NO)-arginine pathway is intimately connected to the release of dopamine (DA) and glutamate (GLU). Moreover, interneurons that express nitric oxide synthase (NOS) are very important for the regulation of DA and GLU neurotransmission and modulate many behavioral and cognitive activities. Therefore, it is suggested that a nitrergic system hyperactivity may act parallel to the increase in DA neurotransmission and decreased GLU in schizophrenia. PPI is a model to access the deficits on the sensorimotor gating that occur in several mental disorders. PPI is characterized by a normal reduction on the startle reflex in response to an intense stimulus (pulse) when this is preceded by a low intensity stimulus (prepulse). Schizophrenic patients and normal volunteers or rodents treated with dopaminergic agonists or glutamatergic antagonists present significant reduction on PPI. This work investigated the ability of a NOS inhibitor, NG-nitro-L-arginine (L-NOARG) in preventing deficits in prepulse inhibition (PPI) caused by non-competitive antagonists of NMDA receptors, memantine, ketamine and dizocilpine (MK-801). : Male Wistar rats (180-300 g) received a pretreatment injection i.p. of L-NOARG (40 mg/kg) or saline 1 h before the test and a second treatment of saline or memantine (10 or 17 mg/kg, i.p., 30 min later, N = 10-15) in Experiment 1, ketamine (6 or 10 mg/kg, s.c., 45 min later, N = 12-16) in Experiment 2, MK-801 (0.3 mg/kg, i.p., 45 min later, N = 7-8) in Experiment 3. Each rat was tested with PPI protocol which consisted on five minutes of acclimation (background noise of 65 dB or 57 dB), followed by 10 presentations of pulse (white noise of 100 dB or 110 dB, 30s of interval, 40 ms) for habituation and then the PPI test itself consisting on pseudorandom presentations of 64 stimuli: pulse (P), pre-pulse (PP, pure tone, 3 kHz, 69, 73 and 81 dB, 20 ms), PP+P (100 ms between stimuli) and null (no stimuli). The level of PPI in each rat was determined by expressing the PP+P startle response (ASR) as a percentage (%PPI) decrease from pulse-alone ASR. Statistical analysis of %PPI and ASR were performed with repeated measures ANOVAs with stimulus intensity (69, 73, 81 dB) as within factor and treatment as between factor. All procedures were previously approved by the Animal Care and Use Committee of University of São Paulo (229/2005). Results: Analysis of %PPI of experiment 1 showed a significant main effects of intensity and Treatment. Post-hoc Duncan test revealed that L-NOARG significantly prevented the PPI deficits caused by memantine at 10 mg/kg on PP intensity of 81dB. Analysis of experiment 2 showed no significant effects of treatment and significant main effect of intensity. Analysis of experiment 3 demonstrated a significant main effect of intensity and a main effect of treatment. The post-hoc Duncan test revealed a significant reduction on %PPI of the group treated with MK-801. Discussion: The non-competitive antagonist of NMDA receptor MK-801 and memantine were able to impair PPI in rats and L-NOARG was able to prevent the memantine effect but not that of MK-801. Our results suggest that memantine, an antagonist lower affinity, can be considered a model that best mimics the deficit in sensory-motor filter observed in schizophrenia. Results support previous data suggesting that the nitrergic system might modulate glutamatergic mediation of sensory-motor filter.

Behavioral changes associated to schizophrenia after abrupt withdrawal from a chronic treatment with clozapine or haloperidol in rats

Neide Derci Silva1,2, Suzy T. Niigaki1,2, Douglas A. Gouveia1,2, Tania Libânio1,2, Mariana B. Calzavara1,2, Vanessa C. Abilio1,2

1Departamento de Farmacologia, Universidade Federal de São Paulo, São Paulo, SP, Brasil/2Laboratório Interdisciplinar de Neurociências Clínicas, Universidade Federal de São Paulo, São Paulo, SP, Brasil

Background: The development of nigrostriatal dopaminergic supersensitivity have been related to the extrapyramidal side effects induced in 20%-30% of patients long-term treated with typical antipsychotics. Conversely, few have been the efforts to investigate behavioral changes associated with the development of mesolimbic dopaminergic supersensitivity. This phenomenon seems to be related to both the manifestations of psychotic symptoms after the withdrawal or reduction of antipsychotic doses, relapse during treatment with them or tolerance to their therapeutic effects. Thus, the objective of this study was to verify the effects of abrupt withdrawal of chronic treatment with a typical antipsychotic (haloperidol) and an atypical one (clozapine) on behavioral parameters associated with schizophrenia: hyperlocomotion (associated to the positive symptoms), impairment in social interaction test (mimicking the negative symptoms), in fear conditioning (associated to emotional processing deficits) and in prepulse inhibition of startle (associated to the sensorimotor gating malfunctioning). : Adult male Wistar rats (n = 10) were treated with vehicle solution, 5 mg/kg clozapine or 3 mg/kg haloperidol for 30 days. Seventy-two hours after the last injection, the rats were subjected to: 1) the social interaction test (locomotion and social performance observed between unfamiliar peers in an open-field); 2) the PPI test (decrease of the pulse-induced startle response when preceded by a low-intensity prepulse); 3) contextual fear conditioning training (presentation of footshocks in a specific context) and testing (freezing response quantified in the same context without footshocks 24h after the training). Results: Animals withdrawn from haloperidol, but not clozapine, had a significant impairment in fear conditioning and an increase in locomotion when compared to control animals. Social interaction and PPI were not altered by any treatment. Discussion: The withdrawal of chronic treatment with a typical antipsychotic (haloperidol) induced behavioral alterations associated with positive symptoms (increased locomotion) and impairments in emotional processing (contextual fear conditioning deficits). As previously seen for the nigrostrial dopaminergic supersensitivity, these behavioral alterations are not induced by atypical antipsychotics.

Role of the dopamine transporter and environmental conditions in an animal model of tardive dyskinesia

Douglas A. Gouvêa1,2, Suzy T. Niigaki1,2, Fernanda F. Peres1,2, Mariana C. Diana1,2, Neide D. Silva1,2, Valéria Almeida1,2,
Vanessa C. Abílio1,2, Rodrigo A. Bressan1, Mariana B. Calzavara1


1Laboratório Interdisciplinar de Neurociência Clínica (LiNC), Universidade Federal de São Paulo, São Paulo, SP, Brasil/2Departamento de Farmacologia, Universidade Federal de São Paulo, São Paulo, SP, Brasil

Background: Tardive dyskinesia, a late-onset adverse effect of long-term treatment with typical antipsychotics, is associated with nigroestriatal dopaminergic supersensitivity and to an increase in oxidative stress. Both phenomena can be influenced by the functioning of the dopamine transporter (DAT) and by stress. This study aims to evaluate the involvement of DAT (by using bupropion, a DAT inhibitor) and environmental conditions (by maintaining the animals in homogeneous or heterogeneous treatment cages) on the development of oral dyskinesia induced by a long-term treatment with haloperidol in rats (an animal model of tardive dyskinesia). : Adult male Wistar EPM-1 rats were used. In experiment 1, animals (n = 10) were treated with vehicle (v), 2 mg/kg haloperidol (h) and/or 30 mg/kg bupropion (b) for 20 days, forming the following groups: v-v, b-v, v-h and b-h. They were kept in heterogeneous cages (composed of rats that received different treatment types). In experiment 2, animals (n = 9-10) were treated with vehicle (v), 3 mg/kg haloperidol and/or 30 mg/kg bupropion (b) for 30 days, forming the groups: v-v, b-v, v-h and b-h, also kept in heterogeneous cages. In experiment 3, animals received the same treatment of experiment 1, but were kept in homogeneous cages (composed of rats receiving the same treatment). Seventy-two hours after withdrawal of each treatment, oral dyskinesia (chewing movements and tongue protrusion) were evaluated. Results: In experiment 1, chewing movements of the group b-v were increased when compared to v-v and v-h). The group b-v also presented an increase in tongue protrusion when compared to v-v and b-h. In experiment 2, chewing movements were increased in the group v-h in relation to v-v; and in the group b-h when compared to v-h, v-v and b-v. There was also a significant increase in the tongue protrusion of the group b-h in relation to b-v, v-h and v-v. In experiment 3, chewing movements were increased in the group v-h in relation to v-v and tongue protrusion was increased in the group b-h in relation to v-v (and b-v. Discussion: The environmental condition seems to directly influence the development of oral dyskinesia given that in the heterogeneous cage the development of oral dyskinesia was observed only with a longer treatment with a higher dose of haloperidol. In addition, the effects of DAT inhibition on the development of oral dyskinesia also vary depending on the cage condition.

Evaluation of the management of antipsychotic-induced sexual dysfunction: a review

Luciana Nunes1,2, Sandra Nunes1, Rodrigo Bressan2, Jair Mari2

1Universidade Estadual de Londrina, Londrina, PR, Brasil/2Universidade Federal de São Paulo, São Paulo, SP, Brasil

Background: Sexual dysfunction is a distressing adverse effect in patients with schizophrenia that are receiving antipsychotic medication and it is prevalent in 50% to 60% of these patients (Ucok et al., 2008; Ucok et al., 2007; Haro and Carulla, 2006). Sexual dysfunction is experienced by patients as significantly more distressing than sedation, extrapyramidal or vegetative side effects (Rosenberg et al., 2003; Lambert et al., 2004). The high prevalence of sexual dysfunction in patients with schizophrenia can significantly affect their life expectancy, quality of life and medication adherence (Heald, 2010a). The purpose of the current rewiew was to seek all the studies that included the strategies for the treatment of antipsychotic-induced sexual dysfunction. : Medline, Cochrane, Lilacs, Embase, and PsycINFO search were evaluated to collect all publications on patients with schizophrenia and spectrum who have reported that antipsychotic induced sexual dysfunction. Open labels or randomized clinical trials were included. The studies’ participants included: both men and women, above 18 years old, suffering from sexual dysfunction (libido, sexual arousal, penile erection/lubrification, orgasm, satisfaction with orgasm, overall sexual satisfaction, menstrual dysfunction and hyperprolactinemia and related symptoms) as measured by criteria defined by the primary authors of the trials. The sexual dysfunction also had to be attributed to the antipsychotic drug therapy, and the patient had to be in use of antipsychotic therapy for at least 4 weeks. Results: Thirty one studies were found: twenty five open label non controlled studies and six randomized controlled clinical trials. The randomized double-blind, controlled studies that were conducted with adjunctive treatment that showed improvement of sexual dysfunction and/or decrease of prolactin levels were sildenafil and aripiprazole. The medication selegiline and cyproheptadine did not improve sexual function. The switch to quetiapine was demonstrated in two randomized controlled studies, one showed improvement in the primary outcome and the other did not. Discussion: This reviewed data has suggested that further well designed, randomized, controlled trials are needed to provide evidence for the effects of different strategies to manage sexual dysfunction and/or  hyperprolactinaemia due to antipsychotic. These trials are necessary in order to have a better compliance and reduce the distress among patients with schizophrenia.

Early antipsychotic treatment in an animal model of schizoprenia

Suzy T. Niigaki1,2, Douglas A. Gouvêa1,2, Lizia Ferreira2, Raquel Levin1,2, Valéria Almeida1,2, Neide D. Silva1,2, Fernanda F. Peres1,2, Mayra A. Suiama1,2, Raí A. Eufrásio2,3, Mariana C. Diana1,2, Mariana B. Calzavara2, Vanessa C. Abílio1,2


1Departamento de Farmacologia, Universidade Federal de São Paulo, São Paulo, SP, Brasil/2Laboratório Interdisciplinar de Neurociências Clínicas, Universidade Federal de São Paulo, São Paulo, SP, Brasil/3Departamento de Fisiologia, Universidade Federal do Rio Grande do Norte, Natal, RN, Brasil

Background: The neurodevelopmental hypothesis of schizophrenia poses that the maturation of the brain in the adolescence is critical to its pathogenesis. In this context, there is a crescent interest if early interventions may prevent this disease. Recently, we have proposed the spontaneously hypertensive rats (SHR) as an animal model to study several aspects of schizophrenia. Based on that, this study aims to characterize beneficial (attenuation of hyperlocomotion and improvement of social interaction – models of positive and negative symptoms, respectively) and/or side effects (development of oral dyskinesia) of an early treatment with antipsychotics in this strain. : Young male Wistar (W) and SHR (n = 10/strain) were treated with saline, 0.5 mg/kg haloperidol, 2.5 mg/kg clozapine or 5.0 mg/kg quetiapine from the 25th to 60th post-natal days. At 3 months of age, oral dyskinesia (chewing movements and tongue protrusion quantified for 10 minutes), locomotion (frequency of locomotion in an open-field for 5 minutes) and social interaction (social interaction parameters observed in pairs of unfamiliar rats with the same strain and treatment submitted to an open-field for 10 minutes). Results: The deficit in social interaction presented by SHR was reverted by the previous treatment with quetiapine (but not haloperidol or clozapine). None of the drugs attenuated the hyperlocomotion presented by SHR. On the other hand, animals withdrawn from haloperidol treatment presented an increase in locomotion. Oral movements were not modified by any of the drugs tested. Discussion: The study of early treatment has been conducted as an attempt to prevent the emergence of schizophrenia in high-risk population. Our results indicate that quetiapine prevents the development of negative symptoms-like behaviors in our model. In parallel, we also verified the absence of oral dyskinesia after early treatment with these antipsychotics (conversely to what is seen in adults long-term treated with typical antipsychotics). On the other hand, withdrawal from a long-term haloperidol treatment induced a behavioral supersensitivity revealed by an increase in locomotion. This hyperlocomotion induced by antipsychotic withdrawal has been related to an antipsychotic-induced supersensitivity psychosis.

Experimental evaluation of anti-dyskinetic potential of topiramate in animal models

Luciana Takahashi C. Ribeiro1, Liliane Minglini B. Ceccon1, Rita de Cassia Carvalho1, Karina Agustini Zanin1, Raphae Wuo-Silva1, Thaís Fernanda Trombin1, Jairo Marcelo Corrêa Leite1, Helaine Arrais Fernandes1, Roberto Frussa-Filho1

1Universidade Federal de São Paulo, São Paulo, SP, Brasil

Background: Tardive dyskinesia is considered the most important side-effect of long-term administration of antipsychotic drugs and is characterized by involuntary movements involving bucco-lingual-masticatory muscles. Recently it has been described anti-dyskinetic properties of gabaergic drugs on animal models of oral dyskinesia induced by reserpine or haloperidol. The aim of the present study is to evaluate the effects of topiramate, an anticonvulsivant drug that acts on gabaergic neurotransmission, in the expression oral dyskinesia induced by reserpine and haloperidol in mice. : Male adult mice (90 days old) were used. Oral dyskinesia was induced with reserpine and haloperidol. Animals were treated with vehicle or reserpine (0.5 mg/kg, s.c.) on days 1 and 3 to induce oral dyskinesia, which characterized by increased vacuous chewing movements. Twenty four hours after the second reserpine injection, the animals were treated with a single injection of vehicle or topiramate (1, 3, 10 or 30 mg/kg, i.p.). In a second oral dyskinesia model, mice were treated daily with vehicle or haloperidol (2 mg/kg, i.p.) during 20 days. Twenty four hours after the last haloperidol injection, the animals were treated with a single injection of vehicle or topiramate (1, 3, 10 or 30 mg/kg, i.p.). In both models, 30 minutes after the treatment with topiramate, the oralfacial movements were quantified during 10 minutes. After that, the general activity was verified in an open field test, during 5 minutes. To evaluate the effects of topiramate per se, control mice were treated only with vehicle or topiramate using the same doses described above. Results: The effective doses of topiramate to reduce the orofacial movements to control levels (15.1 ± 6.8) in the reserpine-treated mice were 10 mg/kg (24.8 ± 6.0) and 30 mg/kg (34.7 ± 6.6). On the other hand, in the haloperidol-treated mice only the highest topiramate dose (30 mg/kg; 29.7 ± 3.5) was effective to reduce the orofacial movements to the levels observed in the control group (15.6 ± 2.9). Topiramate did not change the effects of reserpine and haloperidol in the general activity of mice. Besides, topiramate per se does not affect the expression of orofacial movements. Discussion: Our results show the potential therapeutic effects of topiramate in the treatment of drug-induced tardive dyskinesia. Financial support: Capes.

A comparison between typical and atypical antipsychotics on animal models of negative and cognitive symptoms

Marília Mota Bessa1, Camila Braz Menezes1, Ana Paula Herrmann1, Viviane de Moura Linck1, Elaine Elisabetsky1

1Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brasil

Background: Negative and cognitive symptoms are pivotal to the functional deficiencies and daily difficulties of schizophrenic patients. Although the clinical benefits of typical antipsychotics (TAs) on positive symptoms are undisputed, they lack significant effects on negative symptoms and have a high incidence of motor side effects. The atypical antipsychotics (AAs) were launched on the market with alleged advantages: reduced motor side effects and improvement of positive, negative and cognitive symptoms. Nevertheless, meta-analysis studies did not confirm all of the presumed advantages and lead to the questioning on the cost-benefit of treating schizophrenia with AAs. Relevant to this debate, preclinical data on AAs on animal models of negative and cognitive symptoms are surprisingly scarce. The aim of this study was to compare the effect of TAs (haloperidol and chlorpromazine) and AAs (clozapine, sulpiride, risperidone and olanzapine) on MK801-induced social withdrawn (SW) and working memory (WM) deficit in mice. : Locomotion: Animals (CF1 male mice; n = 10-11) received (ip): saline, haloperidol 0.125 and 0.25 mg/kg, chlorpromazine 1 and 2 mg/kg, clozapine 2 mg/kg, sulpiride 10 mg/kg, risperidone 0.04 and 0.05 mg/kg or olanzapine 0.2, 0.25 and 1.5 mg/kg; 30 min later animals were individually placed in automatic activity box for 10 min. Only doses of antipsychotics that did not alter locomotion were used in SW and WM. Social Withdrawal (SW): mice were individually submitted to 10 min adaptation sessions in the test box at 48 and 24 h before testing. At test day, mice were randomly paired to an unfamiliar partner of same treatment group, and the time spent in social interaction was video recorded for 10 min (The Observer, Noldus). 1 h before the experiment mice (n = 8 pairs) were treated with saline or one of the antipsychotics and 30 min later with saline or MK801 0.3 mg/kg. Working memory (WM): The inhibitory avoidance paradigm was used to assess WM, with a 10 s interval between training and test sessions. 1 h before test, mice (n = 11-20) were treated with saline or one of the antipsychotics, and 30 min later with saline or MK801 0.05 mg/kg. During training (but not test) mice received intermittent shocks (0.3 mA) for 5 s after stepping down from the platform; the difference between training and test latencies was taken as WM measure. Statistics: ANOVA/SNK was used for locomotion and SW. WM was analyzed by Wilcoxon and Kruskal-Wallis/Mann-Whitney. Results: Haloperidol 0.125 mg/kg, chlorpromazine 1 mg/kg, clozapine 2 mg/kg, sulpiride 10 mg/kg, risperidone 0.05 mg/kg and olanzapine 0.2 mg/kg had no significant effects on locomotion (F6,75=2,13; p > 0.05), and were used thereafter. The doses of MK801 were effective in inducing SW and WM deficit (p < 0.05). None of the antipsychotics were able to prevent SW (p > 0.05). Only sulpiride (p = 0.04) and risperidone (p = 0.035) prevented the WM deficit. Discussion: MK801-induced deficits in rodents are considered to have face and construct value in regard to negative and cognitive deficits in schizophrenia. Though the conclusions to be drawn from this study are limited by the use of acute administration and single dose analysis, the data indicates lack of effects on MK801-induced social withdrawn in mice. In regard to working memory deficits, only sulpiride and risperidone were effective in preventing deficit caused by MK801. Considering the diverse phenotype in schizophrenics and the high cost of the therapy with AAs, it is suggested that studies such as these may be useful to design specific clinical trials and ultimately subsidize clinicians to elect the antipsychotic agents that best suits the patient’s needs.

An animal model to predict pdherence to neuroleptic treatment

Daniela F. Fukushiro1, Tatiana C. F. Aramini1, Elisa Mári-Kawamoto1, Fabiana S. Josino1, Jacqueline M. Costa1, Luis P. Saito1, Regina A. Uehara1, Roberto Frussa-Filho1


1Universidade Federal de São Paulo, São Paulo, SP, Brasil


Background
: Lack of neuroleptic treatment adherence is a common problem among schizophrenic patients. There is a close relationship between quality of life of patients and the rate of treatment adherence. Experimentally, adherence to treatment could be predicted by evaluating the aversive properties of these medications in rodents. In the place conditioning model, substances with aversive properties produce avoidance of an environment previously paired with these effects (conditioned place aversion – CPA). We aimed to characterize CPA produced by different doses of the typical neuroleptic haloperidol or the atypical neuroleptic ziprasidone in mice. : Three-month-old Swiss male mice were used. In experiment 1, mice were allocated to 7 groups (N = 12): VEH, HAL0.03, HAL0.1, HAL0.3, HAL1.0, HAL2.0 or HAL3.0. In experiment 2, mice were allocated to 6 groups (N = 12): VEH, ZIP0.1, ZIP0.3, ZIP1.0, ZIP3.0 or ZIP6.0. The animals were subjected to the conditioning procedure in the place conditioning apparatus containing two different main compartments. Mice received an i.p. injection of vehicle (VEH), one of the 6 doses of haloperidol (HAL) or one of the 5 doses of ziprasidone (ZIP) and were confined in the compartment A. Six hours later, these animals received an i.p. injection of vehicle and were confined in the compartment B. A total of 4 sessions with the drug and 4 sessions with vehicle were performed. The control groups (VEH) received vehicle in all of the sessions. Twenty four hours after the last conditioning session, the animals were subjected to the test session in a drug-free state, with free access to both compartments for 15 min. Following 60 min, the animals from experiment 1 were sacrificed and their brains were removed for imunohistochemistry analyses. Expression of the protein product of the neuronal activity marker c-fos was assessed in a number of brain regions of the VEH and the HAL2.0 groups. Results: In experiment 1, animals treated with 0.1 and 0.3 mg/kg haloperidol presented a decrease in the time spent in the haloperidol-paired compartment as compared to the vehicle-paired compartment only at the 0-5 min interval [HAL 0.1: t(11) = 2.3, P < 0.05 and HAL 0.3: t(11) = 2.6, P < 0.05, t-test for paired samples], indicating the development of CPA. However, CPA was more robust in mice treated with 1.0 and 2.0 mg/kg haloperidol because they presented a reduction in the time spent in the haloperidol-paired compartment relative to the vehicle-paired compartment at all the time intervals [HAL 1.0: t(11) = 2.6, 2.3, 2.3, P < 0.05 and HAL 2.0: t(11) = 4.5, 3.5, 3.7, P < 0.05, for 0-5, 0-10 and 0-15 min, respectively, t-test for paired samples]. CPA induced by 2.0 mg/kg haloperidol conferred greater Fos expression in the basolateral and the medial nuclei of the amygdala, the nucleus accumbens shell and core and the lateral septum [t(10) = 9.4, 4.2, 4.8, 7.3, 3.1, P < 0.05, Student’s t-test]. In experiment 2, only the animals treated with 3.0 mg/kg ziprasidone presented CPA at the 0-5 min interval [t(11) = 2.3, P < 0.05, t-test for paired samples]. Discussion: Haloperidol produces CPA especially at the doses of 1.0 and 2.0 mg/kg, and this aversion is possibly related to impairments in animal well being induced by the pharmacological action of this drug. The amygdala, the nucleus accumbens and the lateral septum appear to be involved with the brain mechanisms underlying haloperidol-induced CPA. Conversely, ziprasidone only produced a mild CPA at the 3.0 mg/kg dose, indicating that adherence to this medication should be higher among patients. These results could be of great value in predicting non-adherence to treatment observed in patients treated with neuroleptics. Financial support: FAPESP, CNPq, CAPES, AFIP.

Antioxidant effects of chlorpromazine and clozapine in ketamine-induced schizophrenia model in mice

Luis R. Sampaio1, Dayane P. Araújo1, Francisca T. Rodrigues1, Patrícia X. Gomes1, Márcia C. Silva1, Eliane M. Brito1, Danielle S. Macêdo1, Silvânia M. Vasconcelos1


1Universidade Federal do Ceará, Fortaleza, CE, Brasil

Background: Evidence has shown that neuroinflammation presents an important role in schizophrenia. In this sense, it is necessary to understand the mechanism of action of typical and atypical antipsychotics, as well as, the role of oxidative stress in the pathophysiology of schizophrenia. Based on this, it aimed evaluated the effects of the acute administration of Chlorpromazine (Cp) or Clozapine (Cz), through the dosage of oxidative stress, in the ketamine-induced schizophrenia model in mice. : Female Swiss mice (25-30g; n = 10/group) were used. After acute administration of Cp (1 or 5 mg/kg, ip) or Cz (5 or 10 mg/kg, ip), either alone or 30 minutes before ketamine (Ket) (10 mg/kg, ip), animals were euthanized and prefrontal cortex (PFC) and hippocampus (HC) dissected. Lipid peroxides formation was analyzed by measuring the thiobarbituric-acid reacting substances and was determined spectrophotometrically by the absorbance at 535 nm and expressed as mmol of malondialdehyde (MDA)/g tissue. Catalase activity was measured by spectrophotometry at 230 nm absorbance and expressed as M/min/g protein. For determination of nitrite concentration was used the absorbance at 550 nm via microplate reader. The standard curve was prepared with several concentrations of NaNO2 (ranging from 0.75 to 100 M) and was expressed as μmol/g of protein. For statistical analysis ANOVA with Tukey test as post hoc was used (p < 0.05). Results: Treatment with Ket alone increased the MDA concentration in the PFC (Ket: 3.4 ± 0.1) and HC (Ket: 2.7 ± 0.0) when compared with the control group (1.5 ± 0.1). This effect of Ket was reversed by either pretreatment groups in PFC (Cp 1 + Ket: 2.1 ± 0.1, Cp 5 + Ket: 2.4 ± 0.2, Cz 10 + Ket: 1.9 ± 0.1) and HC (Cp 1 + Ket: 1.6 ± 0.1, Cp 5 + Ket: 1.7 ± 0.2, Cz 10 + Ket: 1.5 ± 0.1). Administration of the Ket alone increased catalase activity in the PFC (Ket: 2.8 ± 0.2) and HC (Ket: 2.4 ± 0.1) when compared with the control group (PFC: 1.4 ± 0.1, HC: 1.3 ± 0.0) and t his effect of Ket was reversed in either pretreatment groups in PFC (Cp 5 + Ket = 1.9 ± 0.2, Cz 10 + Ket: 1.5 ± 0.2) and HC (Cp1 + Ket = 1.6 ± 0.1,Cp 5 + Ket = 1.7 ± 0.1, Cz 5 + Ket = 1.1 ± 0.0, Cz 10 + Ket = 1.5 ± 0.1). Similarly to TBARS and Catalase tests, ketamine alone increased the nitrite concentration in PFC (1.5 ± 0.1) and HC (2.7 ± 0.2) when compared with the control group (1.2 ± 0.0). Pretreatment group in PFC (Cp 1 + Ket: 0.9 ± 0.0, Cp 5 + Ket: 0.8 ± 0.0, Cz 5 + Ket: 1.3 ± 0.0, Cz 10 + Ket: 1.3 ± 0.0) and HC (Cp 1 + Ket: 0.9 ± 0.0, Cp 5 + Ket: 0.8 ± 0.0, Cz 5 + Ket: 1.4 ± 0.0, Cz 10 + Ket: 1.2 ± 0.0) reversed the increase in the nitrite content Ketamine-induced. Discussion: The Ket increased the lipid peroxidation concentration, catalase activity and nitrite content in the brain areas (PFC and HC) as compared with the control, as well as, either Cp or Cz reversed the Ket effects in the oxidative stress. In conclusion, these findings demonstrated pro-oxidative role of Ketamine that was reversed by Cp or Cz.

Behavioral effects of chlorpromazine and clozapine in ketamine-induced schizophrenia model in mice

Luis R. Sampaio1, Dayane P. Araújo1, Ana L. Martins1, José E. Honório-Júnior1, Francisca T. Rodrigues1, Jéssica C. Silva1, Paulo V. Araújo1, Aline S. Monte1, Rita N. Abreu1, Márcia C. Silva1, Eliane M. Brito1, Danielle S. Macêdo1, Silvânia M. Vasconcelos1

1Universidade Federal do Ceará, Fortaleza, CE, Brasil

Background
: The model of schizophrenia induced by ketamine in animals is rooted in understanding the glutamatergic hypothesis of schizophrenia, which relates the NMDA receptor hypofunction to the symptoms of schizophrenia. Based on this model, we aimed to verify the behavioral changes of chlorpromazine (Cp) and clozapine (Cz), in the model of schizophrenia induced by ketamine (Ket) in mice by behavioral tests of open field, rota rod and catalepsy. : Female Swiss mice (25-30 g; n = 10/group) were used. After acute administration of Cp (1 or 5 mg/kg, ip) or Cz (5 or 10 mg/kg, ip), either alone or 30 minutes before Ket (10 mg/kg, ip), behavioral changes were examined through the tests of the open field, rota rod and catalepsy. For open field test, the evaluated parameters were: number of squares crossed (with all four paws) and number of rearing and grooming for five minutes, after one minute of adaptation. The number of falls (up to three drops) and the time spent on the bar for one minute were registered in rota rod. The cataleptic state was considered positive when the animal exceeded 60 seconds on the bar. For statistical analysis, ANOVA with Tukey test as post hoc was used (p < 0.05). Results: Results showed that Ket in the open field test induced hyperlocomotion (65.7 ± 5.6) when compared to the control (44.0 ± 2.9). This effect was reversed by either pretreatment groups (Cp 1 + Ket: 22.0 ± 4.6; Cp 5 + Ket: 0.0 ± 0.0; Cz 5 + Ket: 29.8 ± 5.8; Cz 10 + Ket: 5.1 ± 1.3). The number of rearing (24.2 ± 4.9) and grooming events (11.5 ± 0.4) were increased by Ket when compared to the control (13.7 ± 1.7), (2.1 ± 0.4), respectively. Pretreatment group reversed this effect of Ket for the number of rearing (Cp (Cp 1 + Ket: 0.0 ± 0.0; Cp 5 + Ket: 0.0 ± 0.0) or Cz (Cz 5 + Ket: 18.0 ± 2.4; Cz 10 + Ket: 0.5 ± 0.2)) and the number of grooming events (Cp 1 + Ket: 0.6 ± 0.2; Cp 5 + Ket: 0.0 ± 0.0 or Cz 5 + Ket: 6.2 ± 1.1). In the Rota Rod test, the pre-treatment of Cp (5 mg/kg) (50.1 ± 2.4) or Cz (10 mg/kg) (52.1 ± 3.0) with Ket decreased the time spent in the bar compared to the effect induced by Ket alone (60.0 ± 0.0). In the test of catalepsy, Cp 5 (285.8 ± 7.7) and Cz 10 (248.0 ± 10.28) increased the length of time the animal spent on the bar when compared to the Control group (0.0 ± 0.0). This increase was reverted to Ket only in the group pre-treated with Cz (10 mg/kg). Discussion: The result of our research showed that Ket increased locomotor activity in animals. A significant effect of decrease in locomotion was verified following administration of antipsychotics. The highest doses of Cp and Cz with Ket decreased the length of stay in the Rota Rod test, in comparison to the use of Ket alone. In the catalepsy test, the highest dose of Cp alone and all doses of Cz alone increased the length of time the animal spent on the bar. Only the highest dose of Cp associated with Ket showed an increase in the time the animal stayed on the bar. In conclusion, these findings demonstrated that the mechanism of action of neuroleptics interrelates with the mechanism of action of Ket, via glutamatergic and dopaminergic systems.

Characterization of the dopaminergic system in spontaneously hypertensive rats (SHR) - A new animal model to schizophrenia

Camila M. Santos1, Valéria Almeida1,2, Mariana B. Calzavara1, Hudson de Sousa Buck3, Vanessa Costhek Abílio1,2

1Laboratório Interdisciplinar de Neurociências Clínicas, Universidade Federal de São Paulo, São Paulo, SP, Brasil/2Departamento de
Farmacologia, Universidade Federal de São Paulo, São Paulo, SP, Brasil/3Departamento de Ciências Fisiológicas, Faculdade de Ciências Médicas da Santa Casa de São Paulo, São Paulo, SP, Brasil


Background
: Recently, we found that the SHR strain presents many behavioral changes that are reverted specifically by antipsychotic drugs and potentiated by proschizophrenia manipulations. In this way, we suggested that this strain could be used as an animal model for the study of several behavioral aspects of schizophrenia. Considering that dopaminergic transmission dysfunctions are related to the pathophysiology of this disease, our aim is to quantify parameters of the dopaminergic transmission in SHR (D1 receptors and the enzymes tyrosine hydroxylase -" TH, monoaminoxidase - MAO, and Catechol-O-methyltransferase - COMT) in different brain structures related to schizophrenia. : Male adults Wistar rats and SHR were used (n = 6-8). The animals were sacrificed and their brains removed and frozen. Hemispheres were sectioned (20 mm thickness) in an anteroposterior direction and the sections were placed in coated glasses. For autoradiography analysis of D1 receptors, these slides were incubated with 1nM [3H] SCH23390 (86,0 Ci/mmol, PerkinElmer life Sciences). For immunohistochemical analysis of TH, MAO and COMT, slides were incubated with the specific primary antibody anti-rat for each enzyme. Computational densitometric analysis was performed for determination of the amount of D1 receptors and enzymes in the following regions of interest: prefrontal cortex (CPF), nucleus accumbens (NAcc) core and shell portions, dorsal striatum (ED) and basolateral amygdala (BLA). Results: SHR presented a decrease in the number of D1 receptors in prefrontal cortex and an increase in the amount of COMT in the core portion of the NAcc and a decrease in the stained area for this enzyme on the dorsal striatum when compared to Wistar rats. Discussion: A decrease of D1 density in the CPF is in accordance with the alterations of the dopamine system underlying the pathophysiology of schizophrenia. This decrease was also found in neuroimaging studies with patients with schizophrenia. Interestingly, we also found that D1 gene expression is also diminished in the prefrontal cortex of SHR. Furthermore, the decrease in the stained area on the dorsal striatum may be the result of a structural change in dopaminergic cortico-striatal pathway in the SHR strain. The next step of this research is to extend this characterization to the quantification of D2 receptors and dopamine transporter (DAT).

Cannabidiol: an anxiolytic or an antipsychotic new drug?  

Valéria Almeida1,2, Fernanda F. Peres1,2, Raquel Levin1,2, Suzy T. Niigaki1,2, Antonio W Zuardi3, Jaime E. Hallak3, José A. Crippa3, Vanessa C. Abílio1,2


1Departamento de Farmacologia, Universidade Federal de São Paulo, São Paulo, SP, Brasil/2Laboratório Interdisciplinar de Neurociências Clínicas, Universidade Federal de São Paulo, São Paulo, SP, Brasil/3Departamento de Neurociências e Ciências do Comportamento, Universidade de São Paulo, Ribeirão Preto, SP, Brasil

Background: Cannabidiol, a non-psychotomimetic compound of the Cannabis sativa, has been reported to have central therapeutic actions, such as an antipsychotic and an anxiolytic effects. We have recently reported that SHR present a deficit in social interaction that is specifically ameliorated by atypical antipsychotics. In addition, SHR present an hyperlocomotion that is reverted by typical and atypical antipsychotics, suggesting that this strain could be useful to study negative symptoms (mimicked by a decrease in social interaction) and positive symptoms (mimicked by a hyperlocomotion) of schizophrenia and the effects of potential drugs with an antipsychotic profile. On the other hand, an increase in social interaction in control animals similar to that induced by benzodiazepines is used to screen potential anxiolytic drugs. The aim of this study was to investigate the effects of cannabidiol on the level of social interaction and locomotion presented by Wistar and SHR. : Male adult Wistar (WR) and SHR (9-12/strain/drug) were treated with vehicle, 15, 30 or 60 mg/kg cannabidiol (experiment 1) or vehicle, 1, 5 or 15 mg/kg cannabidiol (experiment 2). Thirty minutes later, the animals were submitted to the social interaction test. In this test, pairs of unfamiliar rats of the same treatment and strain were placed simultaneously into the open-field arena. Social interaction (time spent in active-sniffing and following " or passive " when animals lie next to each other within a distance of 5 cm from skin to skin) and locomotion were scored live during 10 min. Results: SHR treated with vehicle presented a decrease in social interaction time and an increase in locomotion when compared to WR. Treatment with cannabidiol was not able to alter the deficit in social interaction nor the hyperlocomotion presented by SHR at any dose tested. On the other hand, 1 mg/kg cannabidiol increased social interaction presented by WR. Discussion: Our results indicate that cannabidiol present an axiolytic (revealed by the increase in social interaction in WR) but not an antipsychotic profile (absence of effects on the deficit in social interaction and on the hyperlocomotion presented by SHR).


Cognitive and clinical outcomes associated with cannabis use in patients with psychotic disorders

Raphael Braga1, Katherine Burdick1, Pamela DeRosse1, Anil Malhotra1


1The Zucker Hillside Hospital, Glen Oaks, NY, United States

Background: Cannabis is the most widely used illicit substance in Western countries and has a particularly high prevalence in patients with major psychotic disorders. A growing body of evidence suggests a consistent association between cannabis use and psychotic symptoms. Although controversial, several large-scale studies have suggested that cannabis use increases an individual's susceptibility to schizophrenia and other psychotic disorders. Further, several recent studies have sought to assess differences between the clinical presentation of psychotic individuals with a comorbid cannabis use disorder (CUD) and psychotic individuals without a comorbid CUD. These studies have suggested that cannabis use in patients with psychotic disorders may substantially influence cognitive function. The specific nature of this influence, however, has been inconsistent across studies. The objective of the present study was to compare individuals diagnosed with major psychotic disorder with and without a history of CUD on an array of basic neuropsychological measures. : We ascertained a large cohort (N = 594) of patients diagnosed with a major psychotic disorder (schizophrenia, schizoaffective and bipolar disorder with psychotic features) with either no history of a CUD (CUD-"; N = 356) or a history of CUD (CUD+; N = 186). The groups were initially compared on key demographic variables including sex, race, age, duration of illness, parental socioeconomic status, premorbid IQ, education level and global assessment of functioning. After covarying for any observed differences in demographic variables, we compared groups on a brief battery of neurocognitive tests. Results: Compared to the CUD-" group the CUD+ group had significantly better GAF scores (CUD+ 41.8 x CUD- 38, p = 0.006) but less years of education (CUD+ 12.8 x CUD- 13.2, p = 0.033). After correcting for these differences the CUD+ group demonstrated significantly better performance on measures of processing speed (Trail Making Tests A and B, p < 0.0001), working memory (Digits Backward, p = 0.016), verbal fluency (letter and animals, p = 0.029 and p < 0.0001, respectively) and verbal learning (California Verbal Learning Test, p = 0.001). Discussion: These findings suggest that patients with major psychotic disorders and comorbid CUD may represent a higher functioning subgroup of SZ. Future prospective studies are needed to elucidate the nature of this relationship.

Cannabis effects on brain structure in first-episode psychosis


Paulo J. Cunha1, José A. S. Crippa2, Márcia Scazufca3, Paulo R. Menezes4, Robin M. Murray5, Geraldo F. Busatto6, Maristela S. Schaufelberger7

1Instituto de Psiquiatria Faculdade de Medicina da Universidade de São Paulo, São Paulo, SP, Brasil/2Universidade de São Paulo, Ribeirão Preto, SP, Brasil/3Departamento de Psiquiatria, Faculdade de Medicina da Universidade de São Paulo, São Paulo, SP, Brasil/ 4Departamento de Medicina Preventiva e Seção de Epidemiologia, Faculdade de Medicina da Universidade de São Paulo, São Paulo, SP, Brasil/ 5Institute of Psychiatry, London, United Kingdom/ 6Universidade de São Paulo, São Paulo, SP, Brasil/ 7Departamento de Psiquiatria, Faculdade de Medicina da Universidade de São Paulo, São Paulo, SP, Brasil


Background: Cannabis use is particularly frequent in patients with schizophrenia, and it is believed to be associated with a higher risk for the development of the disorder; however, the relationship between cannabis exposure and the structural brain abnormalities present in psychotic patients is still to be elucidated. : Using a 1.5T GE MRI scanner, we examined 28 first-episode psychosis patients (FEP) with cannabis use [(mean exposure = 6.54; ± 4.9 years, weakly or daily use), 2 currently using/26 abstinent for at least 2 weeks; 19 with cannabis as the only drug of abuse], 78 FEP and 80 healthy controls with no history of substance use, drawn from a population-based study in Brazil. Images were processed and analyzed by voxel-based morphometry (VBM) with SPM2. Regional gray matter volumes (GM) were compared between FEP cannabis users, FEP non-users and healthy controls by Analysis of Covariance (ANCOVA). Correlations between GM and age of onset of cannabis use and years of exposure were also conducted; statistical significance was established at p < 0.05 (FWE corrected). Results: Compared to controls, both FEP groups had gray matter (GM) reduction in the left prefrontal cortex (PFC), while a reduction in the right hippocampal GM was present only in FEP patients with no cannabis use. Increased GM volume in the left PFC and in the right hippocampus (this later only at trend level) was found in the cannabis-exposed patients when directly compared with the non-exposed ones. When the analysis was restricted to the schizophrenia group exposed exclusively to cannabis, we found no GM differences between cannabis users versus controls or versus patients without cannabis use. However, this later group still exhibited less GM volume than controls in the hippocampal area. In the schizophrenia group, earlier cannabis use was associated with GM reduction in the left PFC and in the bilateral insula, and with greater GM volume in the right hippocampus, while a longer exposure to cannabis was associated with increase GM in the left hippocampus (although the latter finding only achieved statistical trend level). Discussion: GM reduction in hippocampus and PFC, consistently found in schizophrenia patients when compared to controls, is present in our FEP patients, but is not associated with cannabis exposure. Also, our data suggests that cannabis exposure might be associated with increased GM in hippocampal area. This might be due to differences in cannabidiol/THC proportion and to specific interactions between cannabis and brain morphology in schizophrenia.

Glutamate, serine and glycine plasma levels in schizophrenia patients and first-degree relatives

Márcio T. Cunha1,2, Serdar M. Dursun3, João Paulo Machado-de-Sousa1,4, José A. Crippa1,4, Antonio W. Zuardi1,4, Glen Baker3, Jaime E. Hallak1,4

1Universidade de São Paulo, Ribeirão Preto, SP, Brasil/2Universidade Federal do Triângulo Mineiro, Uberaba, MG, Brasil/3University of Alberta, Edmonton, AB, Canada/4INCT for Translational Medicine, Ribeirão Preto, SP, Brasil


Background: Alternatives to the dopaminergic hypothesis in schizophrenia have been extensively investigated over the last two decades, since therapeutic approaches based on dopamine neurotransmission have limited efficacy. The hypothesis of a dysfunction in the glutamatergic transmission, encompassing not only glutamate itself but also its precursors (serine and glycine) has raised increasing interest. In spite of the several studies investigating alterations in this system in schizophrenia, many questions remain to be answered. The evidence available thus far is contradictory in the sense of clarifying the nature of glutamatergic alterations, or even if they indeed occur. In this study we investigated possible changes in the plasma levels of amino acids in chronic schizophrenia patients on antipsychotic treatment compared to healthy volunteers. Additionaly, we investigated whether amino acid alterations occur in the patients’ first-degree relatives and, in case they do, if it would be possible to use them as possible risk markers for the development of schizophrenia and for the prediction of therapeutic responses. : The sample comprised 15 schizophrenia patients under usual treatment with antipsychotics (responsive) and their first-degree relatives, 15 schizophrenia patients under antipsychotic treatment with clozapine (non-responsive) and their first-degree relatives, and 60 healthy volunteers matched to the other participants according to gender and age. Results: No significant differences were found between the groups concerning serine and glycine. Regarding glutamate, however, non-responsive patients had increased glutamate plasma levels compared to their controls and to responsive patients. Differences were also found between the first-degree relatives, with relatives of responsive patients presenting lower glutamate levels than the others. Discussion: These findings suggest that stabilized treatment-responsive and resistant schizophrenia patients present differences concerning glutamate − but not serine or glycine − plasma levels. The original aspect of this study was the inclusion of first-degree relatives of schizophrenia patients, providing evidence about changes in plasma glutamate levels in this group of healthy participants. Further investigation is required so that these results may be confirmed and better understood.

Differential effects of cre- and post-cocaine treatment with neuroleptics on an animal model of cocaine addiction: implications for the comorbidity of schizophrenia and substance abuse

Daniela F. Fukushiro1, Juliana N. Alvarez1, Luciana T. C. Ribeiro1, Lineane H. F. Zanlorenci1, Roberto Frussa-Filho1

1Universidade Federal de São Paulo, São Paulo, SP, Brasil


Background: It has been demonstrated that repeated administration of psychostimulants may result in augmentation of motor behaviors elicited by the drug in rodents (behavioral sensitization -" BS). Importantly, sensitization-related neuroadaptations, especially in the mesoaccumbens dopaminergic system, seem to play an important role in the process of addiction. Neuroleptics have been shown to attenuate/block, potentiate or have no effects on this phenomenon, depending mainly on the treatment schedule and the doses of neuroleptic used. Thus, short-term treatment with neuroleptics usually attenuates the effects of drugs of abuse because of the antagonism of dopamine D2 receptors, whereas long-term treatment with neuroleptics may potentiate the effects of drugs of abuse due to the development of the dopaminergic supersensitivity phenomenon in response to the chronic blockade of dopamine D2 receptors imposed by these agents. While the former is associated with a possible therapy for drug addiction, the latter is involved with the frequent comorbidity of substance abuse and schizophrenia in humans. In the present study we investigated whether the order of administration of cocaine and haloperidol during long-term treatment could result in differential effects on the development of cocaine-induced BS in mice. : Swiss male mice (3 months old) received two daily i.p. injections, separated by 30 min, for 15 days. Thus, the long-term treatments for the different groups were as follows (N = 15-17): vehicle+saline (or saline+vehicle), vehicle+cocaine (or cocaine+vehicle), haloperidol+saline (or saline+haloperidol), ziprasidone+saline (or saline+ziprasidone), haloperidol+cocaine, cocaine+haloperidol, ziprasidone+cocaine or cocaine+ziprasidone. The doses of haloperidol, ziprasidone and cocaine were 1.0, 4.0 and 10 mg/kg, respectively. Seventy-two hours after the last injection, animals were challenged with an i.p. injection of saline or 10 mg/kg cocaine, placed in an open field and had their locomotion quantified (test session). Fifteen days later, to test for the expression of cocaine-induced BS, all of the animals received an i.p. challenge injection of 10 mg/kg cocaine and had their locomotion quantified in the open-field (retest session). Results: The order of administration of haloperidol and cocaine (but not of ziprasidone and cocaine) during long-term treatment critically determined whether the development of cocaine-induced BS was attenuated or potentiated [one-way ANOVA: F(8,141) = 7.03; P < 0.001]. Haloperidol long-term administration before cocaine injections inhibited cocaine-induced BS (haloperidol+cocaine group: 107.1 ± 17 < vehicle+cocaine group: 193.5 ± 19, Duncan’s test P < 0.05) while haloperidol long-term administration after cocaine injections potentiated this phenomenon (cocaine+haloperidol group: 277.5 ± 20 > vehicle+cocaine group: 193.5 ± 19, Duncan's test P < 0.05). Ziprasidone long-term treatment before or after cocaine injections did not modify cocaine-induced BS (ziprasidone+cocaine group: 218.3 ± 20 = cocaine+ziprasidone group: 164.4 ± 20 = vehicle+cocaine group: 193.5 ± 19). Discussion: These results seem to be due to a complex interaction between cocaine effects and the D2 antagonism as well as the dopaminergic supersensitivity related to haloperidol treatment. This could be of relevance to cocaine addicts who are treated with neuroleptics as well as to the comorbidity frequently seen between schizophrenia and cocaine addiction. Financial support: FAPESP, CNPq, CAPES, AFIP.

Cost-effectiveness of risperidone long-acting injectable versus quetiapine in patients with schizophrenia

Monica Kayo1, Maria L Pereira2, Helio Elkis1
1Programa de Esquizofrenia, Instituto de Psiquiatria, Universidade de São Paulo, São Paulo, SP, Brasil/2Farmacoeconomia, Janssen-Cilag, São Paulo, SP, Brasil

Background: The Risperidone Long Acting Injectable (RLAI) is the first SGA formulation available in injectable, intramuscular and long acting form, enabling administration every two weeks. A 2-year head-to-head study has shown that the rate of relapses and, consequently, rehospitalizations, were significantly lower in patients treated with RLAI, in comparison with oral Quetiapine1. The objective of the present study is to compare the cost-effectiveness of RLAI with oral Quetiapine in the treatment of schizophrenia, using an economic model. : This study was based on a decision-tree analysis, considering the IPAP (International Psychopharmacology Algorithm Project) algorithm2. According to IPAP, patients should be treated in monotherapy, and the medication should be switched in case of therapeutic failure and, in case of two consecutive treatment failures, they are eligible for treatment with Clozapine. We have adapted the IPAP flowchart to the reality of the Brazilian public healthcare system, which states that patients should only receive treatment with SGA after first line treatment with FGA and oral Risperidone, which despite being a SGA, has a cost lower than other SGAs. Cost data were extracted from an analysis of direct cost of hospitalization in a Brazilian public mental health hospital3. As usual in Public Health System, patients considered in this model had previously used Oral Risperidone and were elegible to use other SGA, as well as switch to others. The model was based on a head-to-head, multicenter open study which compared RLAI versus oral Quetiapine in 710 patients with schizophrenia over two years and has demonstrated a rehospitalization rate in patients treated with RLAI of 16.5%, while the patients treated with oral Quetiapine exhibited a rehospitalization rate of 31.3% (p < 0.0001). Only the rehospitalizations due to relapse of psychosis were included. The direct costs included medications, laboratory tests and costs of hospital daily rate. Human resources, general and emergency costs were included in the value of daily rates. Results: In a hypothetical cohort of 1,000 patients followed for two years, the number of hospital days was 3.3 higher in the Quetiapine group, and the number of patients requiring hospitalization in the Quetiapine group was 1.8 higher, which represents 139 patients without hospitalization in the RLAI group in the same period. Mean number of days at hospital was lower with RLAI (32 days) than with Quetiapine (64 days). Discussion: RLAI was the treatment with lower direct cost, generating an annual saving of R$ 1,040.00 per patient in the Public System. A sensitivity analysis has shown that even with a 48% reduction in hospitalization costs RLAI is still a cost-saving option compared to oral Quetiapine, and should therefore be considered by payers in Brazil. RLAI is therefore an important treatment option for patients, physicians and payers. References: 1. Gaebel W et al. Relapse prevention in schizophrenia and schizoaffective disorder with risperidone long-acting injectable vs. quetiapine: results of a long-term, open-label, randomized clinical trial. Neuropsychopharmacology. 2010;35(12):2367-77. 2. www.ipap.org. 3. Daltio CS, Mari JJ, Ferraz MB. Direct medical costs associated with schizophrenia relapses in health care services in the city of São Paulo. Rev Saude Publica. 2011;45(1):14-23.


Challenges for PANSS reliability in international trials: results from psychometric
sata-monitoring in a global schizophrenia trial

William C. Yavorsky1, Ashleigh Defries2, Guillermo DiClemente3, Mark Opler4, Sofija Jovic5, Brian Rothman6

1CROnos CCS, Hamilton, NJ, United States/2Johns Hopkins University, Baltimore, MD, United States/3CROnos CCS, Argentina/4ProPhase LLC, New York, NY, United States/5ProPhase LLC, New York, NY, United States/6ProPhase LLC, New York, NY, United States

Background: The Positive and Negative Syndrome Scale (PANSS) is the primary outcome measure for most global trials in schizophrenia research. It is well-validated and the structured interview guide, alongside detailed severity anchors, makes it preferable to some investigators over other scales. In global trials monitored by the United States National Institute of Health (NIH) it is represented in over 90% of schizophrenia trials (clinicaltrials.gov) in global trials tracked by that body. Despite the wide usage of the scale, the method of administration is variable with by-country effects impacting data integrity. Through the psychometric data-monitoring (PDM) process, idiosyncratic ratings can be detected and addressed. For the PANSS, this often is a function of not only translation, but also of clinical meaning within the culture and tradition versus how it may be conceptualized within the PANSS: this has implications for reliability, validity and sample size calculations. : A global schizophrenia trial using the PANSS to assess severity was evaluated in real-time using psychometric data-monitoring algorithms to determine if there were risks to reliability and validity concerning the administration of the instrument. Psychometric data-monitoring algorithms detect potential inconsistencies and utilize binary and factorial relationships within the instrument and, if inconsistencies are detected then investigators are contacted to discuss the case. This method utilizing this combination of computer-based and expert interface was applied to a large global trial with the aim of improving reliability, validity and overall protocol fidelity. Results: There were 1167 individual visits analyzed from the United States, Russia, Western Europe and India with 47 unique raters. The average rate of remediation was 11% though this was higher at the outset and tended to decline as investigators applied feedback over time. By-country effects were significant (p < .01) with negative subscale items and items that were not directly assessed by the structured interview guide showing poorer reliability. Discussion: Clinician administered psychometric instruments continue to be the primary outcome measures in most schizophrenia trials. There are well-recognized limitations with this type of measurement though this can be mitigated by psychometric data-monitoring. In this study we looked at the results of such a program and the impact on reliability. Although there were particular areas of the scale that showed greater or lesser reliability, these have been well-documented in the past and the approach that differed here was determining why this was the case. The most significant finding being that while there were variable levels of reliability the reasons for this were not related to scale considerations but rather how items were characterized in the individual by-country - clinical traditions. This led to considerable variability until clarified through the data-monitoring process and should be a significant concern to global clinical trial managers.

Six-month outcome of long-acting injectable risperidone in schizophrenia: results from the electronic schizophrenia treatment adherence registry (eStar) in Latin America

Mario Louzã1, Rogelio Apiquian2, Rodrigo Córdoba3

1Schizophrenia Research Program (Projesq), Instituto de Psiquiatria, Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo, SP, Brasil/2Americas University, Behavior and Development Sciences Division, Cidade do México, México/3Nervous
System Research Center (CISNE), Bogotá, Colômbia


Background: Risperidone long-acting injection (RLAI) has demonstrated that its efficacy and safety for the treatment of schizophrenic patients. The aim of this study is to determine the effectiveness of RLAI on the outcome of patients with schizophrenia or schizoaffective disorder enrolled in the electronic Schizophrenia Treatment Adherence Registry (eStar) in Latin America. : We collected data of 79 patients with schizophrenia of schizoaffective disorder (DSM-IV-TR criteria) at baseline, retrospectively for the 12 months prior to baseline and prospectively every three months for 24 months. Number of hospitalizations prior to baseline was assessed by chart review. Efficacy and functioning were evaluated using Clinical Global Impression of Illness Severity (CGI-S), Personal and Social Performance (PSP), and Global Assessment of Functioning (GAF) scores. Relapses, demographics and treatments were also documented. Results: Patients were recruited in Mexico (n = 53), Colombia (n = 15) and Brazil (n = 11). Their mean age was 32.9 years; 65% were male. Seventy-three were diagnosed with schizophrenia and 6 with schizoaffective disorder. The most frequent clinical reasons to start treatment with RLAI were a low adherence (n = 29, 36.7%) and a lack of efficacy of the current treatment (n = 28, 35.4%). The mean dose of RLAI at six months was 34.1 ± 10.2 mg every two weeks. Compared with baseline, the mean CGI-S score significantly improved after six months of treatment (4.19 ± 1.01 versus 3.02 ±1.3, respectively, P < 0.001). GAF scores significantly improved after six months of RLAI treatment (55.7 ± 16.9 versus 69.9 ± 16.1, P < 0.001). PSP score at baseline was 49.4 and improved to 65.8. Only 16 patients (20.2%) presented side effects, which were not serious. The most common side effect was akinesia (n = 4.5%). In addition, three patients showed gastrointestinal disturbances (3.8%) and two patients showed metabolic changes (2.5%). Discussion: RLAI improves symptoms and functionality in patients with schizophrenia and schizoaffective disorder. It is likely that this improvement was due to the improvement of adherence. One of the biggest advantages of long-acting injectable antipsychotics is that they allow for strict monitoring. This is particularly important in Latin American countries, where patients frequently have poor access to mental health services. The main limitations of our study are the lack of a control group and that it was not blinded, which may create a possible observational bias. It is important to establish the relevance of the use of prospective data and that it is necessary to use studies focused on the real world to evaluate adherence because controlled studies, by design, will exclude patients that do not adhere to treatment. Reference: Apiquian R, Córdoba R, Louzã M. Neuropsychiatr Dis Treat. 2010;22:19-26. This study was supported by an unrestricted educational grant from the Janssen.

Treatment of partial and nonadherent schizophrenic patients with
risperidone long acting injection (RLAI) 


Mario Louzã1, Helio Elkis2, Sandra Ruschel3, Irismar Oliveira4, Rodrigo Bressan5, Paulo Belmonte-de-Abreu6, Hamilton Grabowski7, José Carlos Appolinário8

1Schizophrenia Research Program (Projesq), Instituto de Psiquiatria do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo, SP, Brasil/2Projeto de Esquizofrenia (Projesq), Departamento de Psiquiatria da Faculdade de Medicina da Universidade de São Paulo, São Paulo, SP, Brasil/3Hospital Mario Kroeff, Rio de Janeiro, RJ, Brasil/4Universidade Federal da Bahia, Salvador, BA, Brasil/5Universidade Federal de São Paulo, São Paulo, SP, Brasil/6Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brasil/7Hospital Bom Retiro, Curitiba, PR, Brasil/8Janssen Pharmaceuticals, São Paulo, SP, Brasil

Background: About 2/3 of the patients with schizophrenia can be considered nonadherent or partially adherent to oral antipsychotic treatment. The purpose of the present study was to assess the efficacy, safety, and tolerability of switching non-adherent patients with schizophrenia on oral antipsychotic therapy to risperidone long-acting injection (RLAI). : This was a 50-week, multicenter, open-label, non-comparative trial of RLAI in patients with schizophrenia attending seven Brazilian centers who were switched from oral treatment. Patients met the following inclusion criteria: (1) DSM-IV criteria for schizophrenia; (2) age: 18 and 50 years; (3) current treatment with oral antipsychotics; (4) history of nonadherence to antipsychotics within the last 12 months; (5) PANSS ≤ 90 and a PANSS ≤ 4 on each of the following items: conceptual disorganization, hallucinatory behavior, suspiciousness, unusual thought content. Non-adherent patients were those with at least one of the following criteria: (1) hospitalization due to interruption or irregular use of medication; (2) clinical worsening due to irregular use of medication; (3) patient's refusal of taking medication as reported by family members; (4) difficulties to convince patients to accept medication as reported by family members; (5) at least one treatment interruption with worsening of symptoms. The primary efficacy measure was the change from baseline to endpoint for the total score of the Positive and Negative Syndrome Scale (PANSS). Secondary efficacy measures included the change from baseline in: PANSS subscales (negative symptoms, positive symptoms, general psychopathology), Clinical Global Impression (CGI) and Personal and Social Performance Scale (PSP). The Drug Attitude Inventory (DAI-10) was employed to assess patients' attitudes towards psychiatric medication. Adverse events were recorded by the investigator at all visits (weeks: 2, 4, 8, 12, 16, 20, 24, 38, and 50) and severity of movement disorders was evaluated using the Extrapyramidal Symptom Rating Scale (ESRS). RLAI was administered every 2 weeks, beginnig with 25 mg; the dose could be increased up to 50 mg according to the clinician evaluation. Results: Fifty-three patients received at least one dose of RLAI (safety population, n = 53); 2 were excluded from the efficacy analysis (ITT efficacy population, n = 51). The 50-week trial was completed by 29 patients (54.7%). The study group was predominantly male (73.6%) with a mean age of 33.6 years. Final doses of RLAI were 25 mg in 38.1%, 37.5 mg in 38.1% and 50 mg in 23.8% of the patients. The mean PANSS total score was significantly reduced from baseline to endpoint (58.8 ± 1.82 vs. 49.72 ± 2.32; p = 0.0002). Significant improvements were also observed in CGI, PSP, and DAI-10 scales. RLAI was safe and well tolerated. Discussion: RLAI was associated with significant symptom improvements in poorly adherent patients with schizophrenia switched from previous oral antipsychotic medications. The study indicates a favorable tolerability profile, a positive effect on functioning, and adequate treatment acceptance. These findings reinforce RLAI as an alternative to the long-term care of schizophrenic patients with compliance issues. Reference: Louzã MR, Elkis H, Ruschel S, Oliveira IR, Bressan RA, Belmonte-de-Abreu P, et al. Neuropsychiatr Dis Treat, in press. This study was supported by an investigational grant from Janssen Pharmaceutical Companies of Johnson & Johnson, Brazil.

Use of NAC in patients with schizophrenia: preliminary results in private practice

Rodrigo Nicolato1, Tiago Couto1, Anderson Souza1, Dante Galileu1, Thiago Cardoso Vale1, Luiza Martins1, Lafaiete Moreira1, Jonas Jardim1, Marcela Penteado1, Marcos Guimarães1, Leandro Malloy1, Luiz Armando de Marco1, Débora Marques Miranda1, Kim Do2, Humberto Correa1, Marco Romano-Silva1

1Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brasil/2Universidade de Lausanne-CHUV, Lausanne, Switzerland

Background: Many genetic, biochemical and clinical associate the involvement of the redox/glutathione in patients with schizophrenia. NAC (N-acetyl-cysteine) increases, probably, the concentration of glutathione, presumably reduced in patients with schizophrenia and may result in cognitive improvement and reduced negative symptoms and positive up, measured by neuropsychological assessment and the PANSS. : In an open study, we associate, in ten patients with chronic schizophrenia (15 years ± 7,3 years) two grams of NAC per day, the atypical antipsychotics in use and evaluated by neuropsychological assessment and simplified by PANSS, the over six months. Six of the ten patients had lower scores in twenty per cent (± 6), on the subscale of negative symptoms of PANSS. Results: In an open study, we associate, in ten patients with chronic schizophrenia (15 years ± 7,3 years) two grams of NAC per day, the atypical antipsychotics in use and evaluated by neuropsychological assessment and simplified by PANSS, the over six months. Discussion: The neuropsychological assessment showed no simple answer, perhaps be simplified by the follow-up time and the small number of patients. The study was open, not was randomized. We will study the biochemical and genetic involvement of the redox system/glutathione in patients with acute schizophrenia, and a second stage, we try to do a larger study, controlled by relating the association of NAC and the antipsychotic possible to improve, by PANSS and neuropsychological assessment specific.

A randomized, double-blind, cross-over, placebo-controlled trial with lodenafil carbonate in the treatment of erectile dysfunction in utpatients with schizophrenia and spectrum

Luciana Nunes1,2, Sandra Nunes1, Fernando Lacaz2, Rodrigo Bressan2, Jair Mari2

1Universidade Estadual de Londrina, Londrina, PR, Brasil/2Universidade Federal de São Paulo, São Paulo, SP, Brasil

Background: Sexual dysfunction is common in the general population, with estimates of 43% of women and 31% of men reporting some type of sexual dysfunction (Laumann et al., 1999). The prevalence of sexual dysfunction in patients with schizophrenia has been considered to be higher than in the general population, with reported rates averaging 50% to 75% (Kelly, 2004), and the use of antipsychotic drugs is frequently associated with sexual dysfunction. Phosphodiesterase-5 (PDE-5) inhibitors are currently the first line treatment for erectile dysfunction (Goldstein et al., 1998). Our study was the first one to test the use of lodenafil carbonate or placebo in the treatment of erectile dysfunction in a double-blind cross over trial with stable outpatients with schizophrenia and spectrum. : The study design was a randomized, double-blind, crossover, placebo-controlled trial with lodenafil carbonate and it was carried at the Schizophrenia Outpatients Program. The measures used to assess sexual dysfunction were Arizona sexual experiences scale (ASEX) and International Index of Erectile Function (IIFE). The positive and negative syndrome scale (PANSS) and the quality of life scale (QLS) were also used. The measures included the levels of prolactin, estradiol, LH (Luteinizing Hormone), SHBG (Sex Hormone-Binding Globulin), free and total testosterone at baseline and end point. Lodenafil and placebo pills were identical and were used by the patients for 16 weeks. Fifty male outpatients fulfilled criteria for DSM-IV, axis I (SCID-IV) for schizophrenia and spectrum. Results: Ninety four percent (47/50) of the participants completed the study. Lodenafil and placebo produced improvement in ASEX, IIFE, PANSS and QLS scales. ASEX and IIFE scales did not show statistical difference between lodenafil and placebo groups in all sexual domains and total scores. There were no significant differences in the results of PANSS and QLS scales between lodenafil and placebo groups. The results of hormones level revealed no statistically significantly changes over time in level of prolactin, total testosterone, SHBG, estradiol and LH between the treatment with lodenafil and placebo groups. There were no major side effects or adverse drug interactions. Discussion: Lodenafil and placebo were both effective in the treatment of antipsychotic-induced erectile dysfunction. Placebo effect is very important in patients with schizophrenia and this study showed the importance of discussing sexuality and trying to treat sexual problems with these patients.

Does improvement in 2 weeks predict response in 12 weeks? A pilot trial in recent onset schizophrenia

Ivson Tassell Mello1, Monica Kayo1, Vivian Y. Hiroce1, Helio Elkis1

1Universidade de São Paulo, São Paulo, SP, Brasil

Background: Recent reviews led to the hypothesis of early-onset of action of antipsychotics in schizophrenia, within the first 2 weeks. However such data come from randomized controlled trials in chronic schizophrenia. We assessed time to response in subjects with recent onset schizophrenia, to verify whether an early nonresponse to antipsychotics in the first 2 weeks of treatment predicts poor response in 12 weeks. : An open trial in patients with recent onset schizophrenia, following the IPAP algorithm. Subjects were randomized to first generation antipsychotic (FGA) or second generation antipsychotic (SGA) and assessed with PANSS. Early improvement in 2 weeks was defined as 20% improvement of PANSS and response was defined as 30% improvement of PANSS. The IPAP algorithm states that if a treatment with one antipsychotic fails we should switch to a second one, so we have evaluated the effectiveness of switch strategy. Results: Twenty-two patients were included (SGA = 12; FGA = 10); baseline PANSS was 94.16 (± 21.98). Mean age was 30.33 years (± 7.9) and time since diagnosis was 1.6 year (± 2.6). Completer analyses showed an initial improvement ≥ 20% of the PANSS in 50% of the subjects; 41.2% responded in the first 6 weeks and 58.8% did not. At 12 weeks, 76.5% responded to the treatment and 23.5% did not; nine patients achieved remission; 12 did not respond to the first antipsychotic and switched to a second one, with 9 (75%) responding to the second agent. No differences were observed in response rate between FGA and SGA. A χ-2 test between response in 2 weeks (at least 20% improvement at PANSS score) was not correlated with response in 6 weeks [χ-2 = 1.73 (df = 1); Fischer exact test, p = 0.31] nor 12 weeks [χ-2 = 0.60 (df = 1); Fischer exact test, p = 0.57)]. The relative risk of the nonresponders in 2 weeks not responding in 12 weeks was 0.16, among the subjects who completed the trial (N = 16). Discussion: In this pilot trial, early nonresponse did not predict poor response to antipsychotic in 12 weeks regardless the class of antipsychotic used. Even patients without a minimal improvement of 20% at PANSS in 2 weeks showed a final response in 12 weeks. An improvement of 20% is adopted in phase III clinical trials, although this can hardly be considered a minimal improvement according to CGI. Therefore, we prefered to adopt the 30% cutoff, since it is known that open trials tend to have higher response rates. Our sample had a very recent onset illness (mean duration of untreated illness: 1.62 ± 2.60 years), who usually respond better than chronic patients. Our data corroborate the evidence that the biggest improvement occurs in the first 2 weeks (12% improvement), but we did not observe the predictive value of improvement in 2 weeks.

The delay to introduction of clozapine in patients with treatment resistant schizophrenia: a retrospective observational study 
Belquiz S. Avrichir1, Karina Menezes1, Helio Elkis1

1Instituto de Psiquiatria, Faculdade de Medicina da Universidade de São Paulo, São Paulo, SP, Brasil

Background: It is well established that Clozapine is the treatment of choice for refractory schizophrenia and most algorithms and guidelines recommend that such medication should be prescribed after failure of, at least, two trials with antipsychotics. For example, the International Psychopharmacology Algorithm Project (IPAP) (<a href=-http://www.ipap.org/->www.ipap.org) establishes that patients are considered refractory and should receive clozapine after failure of 2 trials with antipsychotics of 4-6 weeks duration, with adequate doses, thus comprising a maximum of 12 weeks of treatment period. However it is well known the introduction of clozapine is delayed and frequently patients are treated with more than two antipsychotic trials generally with antipsychotic polytherapy (1). The aim of the present study is the investigation of the delay of the introduction of clozapine in patients with treatment refractory schizophrenia at the Institute of Psychiatry of University of São Paulo (IPq) as well as the predictors associated with such variable. : Chart review of patients at the IPq provides reliable information regarding previous treatments (2) and among them we chose those patients who fulfilled the criteria for refractory schizophrenia i.e. current use of clozapine and history of previous treatments with conventional or atypical antipsychotics. The period of observations was between 2000 and 2005. Based on the IPAP to be considered refractory patients should be treated with 2 antipsychotic trials comprising a maximum period of 12 weeks (84 days). Therefore the delay of introduction of clozapine was defined as the exceeding period of time in days taking into account the beginning of the first trial. Linear Regression was used to verify the association between delay and predictor variables such as number of adequate trials, total trials, polytherapy trials and demographic variables. Results: Sixty two patients were evaluated. They had a mean (sd) age of 32.20 (10.8) years and had been ill for 11.6 (9.4) years. Twenty three (37%) were women and 39 were men (63%). The mean (sd) of the delay was 250, 3 (346.2) days. Patients who have more than 84 days of delay showed a significant higher number of adequate trials and total trials. Age and duration of illness showed to have no correlation with the delay but male gender was associated with delay to introduce clozapine. Linear regression showed that the total of trials was significantly associated with the delay. The correlation between delay and number of treatments was 0.67 (p < 0.0001). Discussion: The introduction of clozapine was associated with a delay of almost 8 months, instead the expected 3 months (12 weeks). The delay significantly correlated with total treatment trials and male gender. 

Serum Brain-Derived Neurotrophic Factor and Clozapine Daily Dose in Patients with Schizophrenia: A Positive Correlation 

Mariana Pedrini1,2,3,4,5, Ines Chendo1,2, Iria Grande1,2, Maria Ines R. Lobato2,3,5, Paulo Belmonte-de-Abreu2,3,4,5, Camila Lersch2,4,5, Julio Walz1,2,4,5, Marcia Kauer-SantAnna1,2,4,5, Flavio Kapczinski1,2,4,5, Clarissa S. Gama1,2,3,4,5

1Programa de Transtorno Bipolar, Hospital de Clínicas de Porto Alegre, Porto Alegre, RS, Brasil/2Laboratório de Psiquiatria Molecular, Hospital de Clínicas de Porto Alegre, Porto Alegre, RS, Brasil/3Programa de Esquizofrenia, Porto Alegre, RS, Brasil/4INCT for Translational Medicine, Porto Alegre, RS, Brasil/5Programa de Pós-Graduação em Psiquiatria, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brasil

Background: Brain-derived neurotrophic factor (BDNF) plays a critical role in neurodevelopment and neuroplasticity. Altered BDNF signaling is thought to contribute to the pathogenesis of schizophrenia (SZ) especially in relation to cognitive deficits. Clozapine has shown a beneficial effect on cognition in SZ in some studies and a detrimental effect in others. : Two groups of chronically medicated DSM-IV SZ patients (n = 44), on treatment with CLZ (n = 31) and typical antipsychotics (n = 13) had 5 ml blood samples collected by venipuncture. Results: Serum BDNF levels were significantly correlated with CLZ daily dose (r = 0.394, p = 0.028), but not with typical antipsychotic daily dose (r = 0.208, p = 0.496). Discussion: This study suggests that serum BDNF levels are correlated with CLZ daily dose, and this may lead to the cognitive enhancement as seen in patients with SZ under CLZ. Despite the strong evidence that chronic administration of CLZ is effective for patients with SZ, it is still unknown whether atypical antipsychotic drugs regulate BDNF expression. Serum BDNF levels concentration in SZ merits further investigations with regard to the role of neurotrophins in the cognitive response to treatment with CLZ and other atypical antipsychotics.

Efficacy of atypical antipsychotics versus clozapine in patients with refractory schizophrenia: systematic review and meta-analysis

Juliano S. Souza1, Ivson Tassell1, Monica Kayo1, Helio Elkis1

1Programa de Esquizofrenia (Projesq), Instituto de Psiquiatria, Faculdade de Medicina da Universidade de São Paulo, São Paulo, SP, Brasil

Background: Clozapine is considered as the gold standard for the treatment of patients with refractory schizophrenia, based upon its well established superior efficacy against typical antipsychotics. Nevertheless, data on other atypical antipsychotics are still scarce or divergent for this population. Considering that clozapine use is associated to several caveats, there is an unmet need for safe and efficacious alternative therapeutic approaches for refractory schizophrenia. : It was conducted a systematic review of randomized clinical trials (RCTs) comparing clozapine to other atypical antipsychotics in patients with refractory schizophrenia. Metanalysis assessing the efficacy of interventions were performed. Efficacy was measured by psychotic symptoms scales. Response to treatment was measured by the percentage of responders or by mean change or endpoints values of such scales. Whenever possible, metanalysis comparing clozapine to other specific atypical antipsychotic were performed. Effect sizes were shown as relative risks (RR) or weighted or standardized mean differences (MD), with 95% confidence intervals. The fixed effect model was used, unless studies were considered heterogeneous. Sensivity analyses were performed with the exclusion of studies which had included intolerant patients along with true refractory patients. Results: Eleven RCTs were included, figuring 1182 patients. Eight metanalysis comparing clozapine and atypical antipsychotics considered as a group were performed, five comparing clozapine to olanzapine, and one comparing clozapine to risperidone. Considered as a group, it was not possible to determine different effect sizes between atypical antipsychotics and clozapine for any general measure of psychotic symptoms. Pooled mean change and endpoint PANSS and BPRS scores metanalysis presented a zero mean difference (MD = 0.00, CI95%= -0.12, 0.11). Atypical antipsychotics were shown to be marginally superior to clozapine for negative symptoms, measured by PANSS negative symptoms subscale endpoint scores (DM = 1.96, CI95%= -3.44, -0.48). Specific comparisons between clozapine and olanzapine pointed to no differences between these agents, except a marginally significant higher effect size favoring olanzapine for negative symptoms, using pooled PANSS negative subscale endpoint scores (DM = -1,43,95% CI: -2,56,-0,30). Olanzapine results might have accounted for most of the results of atypical antipsychotics when combined as a group. Studies which compared clozapine to olanzapine had relatively high mean final olanzapine doses (means ranging from 17.2 mg/d to 33.6 mg/d), what might have influenced the results. Discussion: Atypical antipsychotics, particularly high dose olanzapine, can represent an alternative therapeutic approach to patients with refractory schizophrenia. However, clozapine still remains as the therapeutic alternative with the strongest body of evidence supporting its use among patients with refractory schizophrenia.

rTMS in schizophrenia: literature review

Tiago Couto1, Rodrigo Nicolato1, Thiago Cardoso Vale1, Dante Galileu1, Maria Carolina Lobato1, Antônio Alvim1, Lafaiete Moreira1, Jonas Jardim1, Hélio Lauar1, Mohamad Saleh1, Marcela Penteado1, Marcos Guimarães1, Luiz Armando de Marco1, Leandro Malloy1, Marco Romano-Silva1, Humberto Correa1

1Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brasil

Background: Patients with schizophrenia often have low or no response to antipsychotic therapy currently available. Few treatment alternatives for these patients. There has been an increase in studies focused on specific symptoms of refractory schizophrenia. Evidence suggesting that repetitive transcranial magnetic stimulation may be effective in negative symptoms begin to appear, however, many of the studies to date have small samples and the results are still controversy. : We conducted a systematic review of 20 studies selected prospective studies evaluating the efficacy of rTMS at high frequency in the dorsolateral prefrontal cortex in the treatment of negative symptoms in refractory schizophrenia. Results: The results highlight the need for future controlled studies with larger sample sizes and with different stimulation protocols to verify real effectiveness of rTMS on negative symptoms of schizophrenia. Discussion: At this point, begin study of 20 schizophrenic patients with auditory hallucinations and negative symptoms, which also will undergo functional neuroimaging such as PET and extensive neuropsychological evaluation will also occur, try to answer questions about the real efficacy of rTMS, associated with the use of antipsychotics, the reduction of auditory hallucination, and negative symptoms and on cognition, and relate a possible improvement to the findings of neuroimaging and neuropsychology.

Effects of donepezil on oral dyskinesia induced by reserpine or haloperidol

Liliane Minglini B. Ceccon1, Luciana Takahashi Ribeiro1, Rita de Cassia Carvalho1, Anderson Bruno Pellanda1, Ivan Barraviera Masselli1, Marcelo Cortês Cavalcanti1, Thiago Henrique de T. França1, Tatiana Cristina Fer Aramini1, Aline Ribeiro Borçoi1, Luciano Fernandes do Santos1, Roberto Frussa-Filho1

1Universidade Federal de São Paulo, São Paulo, SP, Brasil

Background: Tardive dyskinesia (TD) is a frequent side effect of treatment with classical neuroleptic drugs. Clinical reports suggest antidyskinetic properties of cholinergic agonists while anticholinergic agents can exacerbated the manifestation of TD. The present study investigates the effects of different doses of donepezil (acetylcholinesterase inhibitor) on the manifestation of reserpine or haloperidol-induced oral dyskinesia in mice. : The orofacial dyskinesia was induced according with two experimental models (reserpine or haloperidol). Animal model of reserpine-induced oral dyskinesia, male EPM-M2 mice received two injections of control solution or of 0.5 mg/kg reserpine separated by 48h. In the animal model of haloperidol-induced oral dyskinesia, the animals were treated daily with intraperitoneal injections of vehicle or haloperidol (2 mg/kg) for 20 days. In both models, twenty-four hours after the last injection (reserpine or haloperidol), animals were acutely treated with control solution or donepezil (0.3, 1.0 or 3.0 mg/kg, ip) and were observed for quantification of oral dyskinesia and general activity in an open-field. In order to verify the effects of donepezil per se on oral dyskinesia and general activity, male EPM-M2 mice were acutely treated with control solution or 0.3, 1.0 or 3.0 mg/kg donepezil and observed for quantification of oral dyskinesia and general activity. Results: The highest dose of donepezil completely abolished the manifestation of reserpine or haloperidol-induced oral dyskinesia. None of the doses of acetylcholinesterase inhibitor modified spontaneous locomotion frequency or oral movements. Discussion: These results support the potential therapeutic use of donepezil in the treatment of oral dyskinesias.

Prevalence of tardive dyskinesia and all-cause mortality amongst patients in a large psychiatric Institute in Rio de Janeiro

Eduardo S. Martins1, Ana L. Z. Rosso2, Evandro S. F. Coutinho3, Clive E. Adams4, Gisele Huf1

1Instituto Nacional de Controle de Qualidade em Saúde, Fundação Oswaldo Cruz, Rio de Janeiro, RJ, Brasil/2Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, Brasil/3Escola Nacional de Saúde Pública, Fundação Oswaldo Cruz, Rio de Janeiro, RJ, Brasil/4Nottingham University, Nottingham, ME, United Kingdom

Background: Tardive dyskinesia is one of the most disturbing adverse effects of the older antipsychotics. It is characterized by abnormal, repetitive and involuntary movements and tends to be a chronic condition. Systematic reviews have identified many randomized studies but few are of adequate power to properly investigate the effects of any reputed treatment. Since the advent of the new generation of antipsychotics this area of research has become less active, however, clinicians and researchers continue to have responsibilities towards this large group of elderly mentally ill people with this iatrogenic, disfiguring and distressing problem. This study aimed to estimate the prevalence of tardive dyskinesia and survival in a 7-year period in patients living in an institution for chronic mentally ill people. : A cross-sectional study was carried out with 100 inpatients randomly selected (simple random sample) from those living in Institute Juliano Moreira, Rio de Janeiro, Brazil, during October 2003. Patients were scored using the “Abnormal Involuntary Movements Scale” – AIMS. Prevalence of tardive dyskinesia and 95%CI were stratified by sex, age and length of stay. Data on all-cause mortality were obtained in October 2010. First, we compared the mortality profile among patients with and without tardive dyskinesia using Kaplan-Meier curve and the log-rank test to calculate statistical significance. Cox model was used to fit the co-variables. Data were analyzed using Stata 10. Results: Of the 100 patients selected at random all were available in the hospital and everyone was possible to examine using the AIMS. The sample population was very similar to the source population, except for a slight higher prevalence of women, they corresponded to more than two thirds of the sample. Mean age was 66 (SD 10) and mean length of stay in the hospital was 38.4 years (SD = 7.7). Sixty five people were in current neuroleptic use, and among them, 9 (14%) were in use of atypical antipsychotic drugs. The total prevalence of tardive dyskinesia (TD) was 34% and reliability for diagnosis was 0.85 (95%CI 0.64-1.00). Higher prevalence of TD was positively associated to age and length of stay. No specific treatment for TD was found on the notes. The seven-years cumulative mortality was 30% and the most frequent referred causes for death were lung problems, cancer and diabetes mellitus. No clinically important differences were found on mortality curves of patients with and without TD (p-value = 0.86) and after controlling for sex, age and time since admittance, the hazard rates remained without statistical significance. Discussion: Prevalence is high, but similar to other studies. Those people with TD were not getting any specific treatment for this condition at any time. Unlike other studies, this one could not detect association between TD and higher mortality. Despite the large number of institutionalized patients in Brazil, this is the first study on the prevalence of TD. Nevertheless, the survey was conducted in Rio de Janeiro, and caution may be necessary to extrapolate its findings. Clinical trials have failed to indicate an effective treatment for this unpleasant condition. Nevertheless, the large majority of trials have randomized a very small number of patients, and it makes difficult to properly evaluate the interventions.

Increased Total Reactive Antioxidant Potential (TRAP) in chronic obese patients with schizophrenia: a comparison between obese and non-obese

Bruna S. Panizzutti1, Gabriel R. Fries1,2, Raffael Massuda1,2,3, Karine Zórtea1,2,3, Matheus A. B. Paquali4, Jose C. F. Moreira4, Carlos E. Schnorr4, Clarissa S. Gama1,2,3

1INCT Translational Medicine, Hospital de Clínicas de Porto Alegre, Porto Alegre, RS, Brasil/2Programa de Pós-Graduação em Psiquiatria, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brasil/ 3Programa de Esquizofrenia, Hospital de Clínicas de Porto Alegre, Porto Alegre, RS, Brasil/4Departamento de Bioquímica, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brasil

Background: Obesity has been consistently associated with increased morbidity and mortality due to cardiovascular disease, diabetes and metabolic syndrome, and it is highly prevalent in patients with schizophrenia (SZ). Evidences suggest that oxidative stress (OS) plays a key role in the pathophysiology of SZ, and its association with obesity has been already reported. We sought to compare OS parameters in obese and non-obese chronic stabilized schizophrenic patients. : Forty-five DSM-IV patients with SZ were enrolled (15 obese and 30 non-obese). Obesity was defined as a body mass index (BMI) ≥ 30. Serum thiobarbituric acid-reactive substances (TBARS), protein carbonyl content (PCC) and total reactive antioxidant potential (TRAP) were measured and compared between groups. P values lower than 0.05 were considered to be significant. Results: No significant differences between age, sex, illness duration, daily antipsychotic dose in milligrams of chlorpromazine equivalents and total Brief Psychiatric Rating Scale (BPRS) scores were found between groups. TBARS and PCC were not different between groups (TBARS - U = 169.5, Z = -1.336, p = 0.181; PCC - U = 153.5, Z = -1.722, p = 0.085), but TRAP was significantly increased in obese patients (67.36 ± 30.82) when compared to non-obese patients (67.36 ± 30.82; U = 143, Z = -1.974, p = 0.048). Discussion: Total antioxidant defense is increased in obese patients with SZ when compared to non-obese. It seems that obese group performs an antioxidant action reactive to obesity in this sample. Further studies are required to explore these data and clarify the oxidative mechanisms involved in the SZ-associated morbidity.

Evaluation of weight gain and metabolic syndrome in patients with schizophrenia taking antipsychotics


Rodrigo Nicolato1, Leandro Malloy1, Tiago Couto1, Dante Galileu1, Fabrício Bíscaro1, Marcela Penteado1, Marcos Guimarães1, Lafaiete Moreira1, Jonas Jardim1, Anderson Souza1, Maria C. Lobato1, Isabela Wending1, Antônio Alvim1, Thiago Cardoso Vale1, Humberto Correa1, Marco Romano-Silva1

1Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brasil

Background: One big question about the treatment based on antipsychotics is the possibility that some patients with schizophrenia would be vulnerable to weight gain, with possible metabolic repercussions, such as diabetes. The genetic, clinical, neurological, cognitive and psychiatric disorders may contribute to the possible weight gain. : 60 patients with schizophrenia were consecutively evaluated by a psychiatrist and an endocrinologist, with t of psychiatric interview, neurological examination, biochemical tests, application of PANSS, metabolic and endocrinological evaluation, relating these parameters with the use of antipsychotics, considering the statistical significance at p value less than 0.05. Results: The atypical antipsychotics olanzapine and clozapine antipsychotics were more associated with weight gain. The negative symptoms were associated more frequently with weight gain and thirty-five percent of patients had metabolic syndrome. Discussion: The results confirm literature. The genetic study may be needed for better understanding and greater number of patients may be needed to confirm these findings.

Significant weight loss in patients with schizophrenia in long-term hypocaloric diet

Karine Zortéa1, Lísia R. Guimarães1, Brisa S. Fernandes1, Clarissa S. Gama1, Paulo S. Belmonte-de-Abreu1

1Universidade Federal do Rio Grande do Sul, Hospital de Clínicas de Porto Alegre, Porto Alegre, RS, Brasil

Background: Schizophrenia (SZ) is associated with increased obesity and excess morbidity and mortality from cardiovascular disease. Behavioral strategies aimed at lifestyle modification have proven effective for weight loss in general population but have not been studied adequately in schizophrenia. The aim of the present study was to evaluate changes in weight and body mass index (BMI) of patients with schizophrenia following a long-term nutritional treatment. : We conducted a retrospective study involving 42 individuals with SZ on nutritional treatment from the Schizophrenia Program of a major teaching and public hospital in Porto Alegre, Brazil (Hospital de Clinicas de Porto Alegre − HCPA), from 2004 to 2010. The nutritional treatment consisted of a hypocaloric diet prescription, a low-fat diet with diary intake of 20 to 25 kcal/kg/day. Medical charts were reviewed after obtaining institutional approval and data collection was conducted for weight, height, BMI, age, gender and diet prescription. Weight and BMI were evaluated at baseline of nutrition treatment, after six months, after twelve months and at the time of data collection. Results: There was a significant weight loss and significant decreased in BMI when compared each group to baseline (p < 0.001). Discussion: Our approach allowed to demonstrate that nutritional interventions can promote a significant weight loss in SZ and prevent antipsychotic drug-induced weight gain. These results support the importance of nutritional intervention in patients with SZ and bring evidences that weight loss remains along the time.

Increased body fat (BFP) associated to decreased level of functioning in patients with schizophrenia

Karine Zortéa1, Lísia R. Guimarães1, Cátia Schmitt2, Paulo S. Belmonte-de-Abreu1

1Universidade Federal do Rio Grande do Sul, Hospital de Clínicas de Porto Alegre, Porto Alegre, RS, Brasil/2Hospital de Clínicas de Porto Alegre, Porto Alegre, RS, Brasil


Background: To test an association between body fat percentage (BFP) and different the aspects of daily functioning assessed by the Function Assessment Scale (FAST) in stable outpatients diagnosed with DSM-IVTR schizophrenia at the Schizophrenia Program from a major teaching Hospital (Hospital de Clinicas de Porto Alegre (HCPA)) in south Brazil. : Demographic information, type and dose of medication, anthropometric data (BMI and BFP) and functionality (FAST) were collected in 100 patients, 71% of which men. The study was approved by the hospital’s Ethics and Research in Health Committee. Results: It was observed a positive correlation between body fat percentage and the total score of the FAST scale (p = 0.037). When analyzing categories, BFP was inversely associated to autonomy (p = 0.05) and with leisure (p < 0.01). The items in the scale which were correlated with body fat percentage were the following: 3 (house shopping) 21 (sexual relationship), 22 (self-assurance), 24 (overall leisure). Discussion: The association of increased body Fat with overall decrease of functioning, specially in autonomy, sexuality and leisure draws attention to the importance of adequate monitoring of nutritional status, so patients and caregivers could understand the necessity of keeping and monitoring diet, in order to increase functionality. It also brings the issue of the importance of adequate nutrition for better coping with schizophrenia.

Lifestyle intervention for weight gain management in schizophrenia - A multicentric randomized controlled trial

Cecília Attux1, Larissa C. Martini1, Hélio Elkis2, Sérgio Tamai3, Andréa Freirias3, Maria G. Camargo2, Mário D. Mateus1, Daniela F. Canguçu1, Jair J. Mari1, André F. Reis4, Rodrigo A. Bressan1

1Departamento de Psiquiatria, Universidade Federal de São Paulo, São Paulo, SP, Brasil/2Instituto de Psiquiatria, Universidade de São Paulo, São Paulo, SP, Brasil/3Santa Casa, São Paulo, SP, Brasil/4Departamento de Clínica Médica, Universidade Federal de São Paulo, São Paulo, SP, Brasil

Background: Overweight and obesity are important features of schizophrenia leading to increasing physical morbidity and mortality. Lifestyle strategies are effective ways to control weight gain but for patients with schizophrenia are more challenging due to negative symptoms, poor dieting habits, cognitive deficits and the side effects of antipsychotic medications. The objective was to evaluate the efficacy of a lifestyle intervention for weight gain management in patients with schizophrenia. : A multicentric randomized trial was conducted to compare a 12-week lifestyle intervention group (LI) (nutrition counseling, lifestyle, physical activity and self-esteem) with standard care (SC). The primary outcome was weight and body mass index (BMI) at 3 and 6 months. During the study all patients were maintained in regular psychiatric treatment and were followed up for 6 months. Weight, waist circumference, blood pressure, fasting blood glucose, insulin and lipid profile were obtained as secondary outcomes. Data were analyzed using the intention to treat analysis (ITT). Results: 160 patients were enrolled in the study (81 intervention x 79 standard care). After 3 months, patients under the LI group presented a decrease of 0.3 kg (CI 95% -1.08 to 0.48) and those under standard care showed an increase of 0.5 kg (CI 95% -0.32 to 1.24; p > 0.05). After 6 months, the LI group presented a decrease of 1.2kg (CI 95% -0.01 to 2.41) while the SC had an increase of 0.47 kg (CI 95% -0.51 to 1.45; p = 0.043). Discussion: The lifestyle intervention was associated with a statistically significant weight decrease after 6 months of follow-up. Although the weight reduction in the intervention group was small, the standard care group maintained tendency to increase weight. Lifestyle interventions are important strategies to avoid the tendency to increase weight in patients with schizophrenia.

Pro12Ala polymorphism in PPARg2 gene, the metabolic syndrome and response to metformin in clozapine-treated schizophrenia patients


Erika C. Fernandez1, Edgardo J. Carrizo1, Lisset D. Connell1, Trino J. Baptista2

1Institute of Clinical Research "Dr. Américo Negrette", Zulia University Medical School, Maracaibo, Zulia, Venezuela/2Department of Physiology, Los Andes University Medical School, Merida, Merida, Venezuela

Background: A great concern currently exists about the high frequency of obesity and metabolic syndrome in atypical antipsychotic (AAP)-treated schizophrenia (SCHIZ) patients. Polymorphisms of genes involved in metabolic regulation are currently investigated in search of non-environmental predisposing factors. In this study, we assessed the frequency of the Pro12Ala polymorphism of the PPAR-g2 gene in clozapine-treated SCHIZ patients, its relationship with the metabolic syndrome (MS) and the response to the antidiabetic agent metfomin (500 mg BID). : Fifty six patients (26 received metformin and 30 received placebo for 14 weeks) and 49 healthy controls were evaluated according to the ATP-III criteria for the MS. PCR-RFLP analysis for determination of the genotype with regard to the Pro12Ala polymorphism of human PPAR-g2. Results: The genotype distribution was as follows: SCHIZ group: Pro/Pro 43 subjects (77%); Pro/Ala 13 subjects (23%); control group: Pro/Pro 37 subjects (76%); Pro/Ala 12 subjects (24%). Neither of the figures deviated from the Hardy-Weinberg equilibrium. In controls, the frequency of the MS was significantly higher in the Pro/Pro group: 51.4% vs. 24%, p = 0.1, which also displayed higher levels of triglycerides (p = 0.02) and LDL cholesterol (p = 0.051). In the schizophrenia group the highest frequency of the MS was observed in the Pro/Ala genotype: 53.8 vs. 16.3%, p = 0.006, which also displayed significantly higher levels of glucose, triglycerides, total cholesterol (p < 0.05) and HOMA-IR index (p = 0.052). No differences in the response to metformin were observed between the two genotypes. Discussion: An opposite pattern of association between the MS and the PRO12Ala polymorphism of the PPAR-g2 gene was observed in schizophrenia patients and healthy controls. This finding must be replicated in more powered studies. The lack of association between PPAR-g2 gene polymorphisms and metformin response contrasts with results considering polymorphisms in the leptin gene observed in the same clinical population (1). Reference: 1. Fernández E, et al. Schiz Res. 2010;121(1-3):213-7.

Weight gain in schizophrenic patients on olanzapine therapy

Marina S. Balbão1, Regina H. C. Queiroz1, Eliane C. Arantes1, Sonia A. C. Dreossi1, Ana M. S. Durão2, Jaime E. C. Hallak2,3

1Departamento de Clínica, Análises Bromatológicas e Toxicológicas, Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, SP, Brasil/2Departamento de Neurociências e Ciências do Comportamento, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, SP, Brasil/3Instituto Nacional de Ciência e Tecnologia, Medicina Translacional CNPq, Ribeirão Preto, SP, Brasil


Background: Schizophrenia is a relatively common, chronic, and frequently devastating neuropsychiatric disorder, affecting about one percent of the world's general population. The olanzapine is an antipsychotic atypical drug used in the treatment of the schizophrenia. Like adverse effects made a list to his use, they find obesity, hiperlipidemia, diabetes mellitus type II and high blood pressure, being able to bring in the development of metabolic syndrome. The mechanisms by which some atypical antipsychotic medications contribute to weight gain are poorly understood. It is believed that the interaction is probably multifactorial, determined by increased appetite, consumption and energy storage, energy expenditure, metabolic and endocrine diseases. Many neuropeptides and hormones involved in homeostasis and body weight regulation. Among these anorexigenic peptides leptin and neuropeptide PYY and the orexigenic peptides ghrelin and neuropeptide NPY, have a crucial role in energy balance (modulation of hunger and satiety) and appetite during treatment with some atypical antipsychotics. Thus, this study aims to investigate levels of peptides related to appetite regulation in patients with olanzapine therapy in order to establish a possible mechanism of action for weight gain. : Thirty schizophrenic patients were evaluated at five times, before starting therapy with olanzapine, after one month, two, three, nine and twelve months of medication. The determination of peptides leptin, ghrelin, PYY and NPY neuropeptides were made ​​using the method of enzine immunoassay. Results: The levels of orexigenic peptides showed a statistically significant increase, while levels of anorectic peptides showed subtle reduction, but without statistical significance. Discussion: Thus, we can intuit that these peptides are closely correlated with weight gain resulting from the use of antipsychotic olanzapine. This finding is extremely relevant because it may explain the weight gain during antipsychotic therapy is the stimulation of appetite and hunger induced by an increase in orexigenic peptides.

The participation of individuals with schizophrenia in classes to medical school students of Unifesp (Federal University of Sao Paulo)

Jorge C. Assis1, Wagner B. Souza1, Jose A. Orsi1, Rodrigo A. Bressan1

1Programa de Esquizofrenia (PROESQ), Universidade Federal de São Paulo, São Paulo, SP, Brasil

Background: The teaching of Psychiatry in the medicine program is done or through expositive classes or classes with the participation of people that have the symptoms in this study. Since 2005, the teaching of schizophrenia at Unifesp is given through expositive classes and the participation of individuals with schizophrenia, but are stable and are the agents in the educational process of the mental disorders. This initiative purpose that individuals with schizophrenia participate as lecturers in the classes about this theme, offered to the students of the third year of medicine. The classes have four-hour duration; the last hour is reserved to the participation to the three users speaking about their history and vision about schizophrenia and the dialogue with the students. : In 2005, the professor invited the individual with paranoid schizophrenia to participate of the classes to four groups of students of the third year of medicine. This format was validated during the year of 2006. In 2007, it was invited to participate a second individual with schizoaffective disorder. And from 2008, it was invited the third individual with refractory schizophrenia. These three people participate of this educational action since then, also in 2009 and 2010. In 2008 and 2009 it was done a intervention in two groups and it was not done in two groups, to validate the effect of intervention with the application of the scale Student’s attitudes towards people with schizophrenia, developed by Schulze, et al. (2003). These individuals participate of anti-stigma activities of one partnership between PROESQ – Schizophrenia Program of São Paulo Federal University (Unifesp) and ABRE – Schizophrenia Brazilian Association. They are stable in relation to the illness and, fell that their participation are welcomed and relevant to the students. They are accompanied before and after the interventions, where they can be welcomed in their perceptions and effects of intervention. Results: The users fell themselves more comfortable and welcomed, as by the professor as by the students, to participate as authors of the educational intervention. They understand that their participation are important to deconstruct stigma and to contribute in the teaching of the theme. It was a significant increase of the insights about the illness in function of attending the conceptual classes about the schizophrenia. The students, beyond of learning the main characteristics of schizophrenia with the proper conceptual rigidity, have the opportunity of listening testimonies given to individuals with three different manifestation of the illness, and they can make questions to the lecturers that propitiate a differentiate understanding of the lively aspects that involve the experience though the face-to-face dialogue. The professor, who conducts this intervention with care, has the opportunity to offer a differentiated and effective educational proposal. Discussion: This educational activity is one of the possibilities that PROESQ can offer to the medical teaching, as result of its functioning form that propitiate and welcome the empowerment of its users, as the narrow partnership with ABRE – Brazilian Schizophrenia Association. This activity was idealized and brought to practice by the Coordinator of PROESQ, that gives classes, with the sustained objective through the years to offer a educational practice more complete and humanistic.

Empowerment and schizophrenia: the experience of the acolhimento group at Programa de Esquizofrenia (PROESQ), Federal University of São Paulo (Unifesp)  


Fernanda A. Pimentel1,2, Anna M. P. Miranda1,2, José A. Orsi1,2, Fernanda V. Santos1,2, Cecilia C. Villares1,2

1Programa de Esquizofrenia, São Paulo, SP, Brasil/2Universidade Federal de São Paulo, São Paulo, SP, Brasil

Background: Beyond the suffering caused by medical issues intrinsic to the disease, patients with schizophrenia also suffer the impact this issue in their lives, resulting in a decrease in their quality of life. With this in mind, the Acolhimento Group for people with schizophrenia was established in 2005 through a partnership between the PROESQ Unifesp and the Brazilian Association of Relatives, Friends and People with Schizophrenia (ABRE). It is an open group, not only for people in treatment at PROESQ but also for those who treat in other departments of health network. It happens once a week with an one hour duration. It is a potential opportunity for exchanges and discussions, where from their own experience and listening to other’s experience, the patients can discuss issues relating to the experience of illness and its consequences in everyday life Its goals: to provide participants with a welcoming environment and support for trade, thinking and looking for alternatives in the face of adversity, strengthen participants to confront the difficulties, given its uniqueness (empowerment) to encourage the construction and activation of a network support within and outside the group. : The coordination of the group is divided by two occupational therapists in partnership with schizophrenic carriers who assume a role as facilitators in discussions. The facilitators are there to make easier the communication and assist the group in meeting its objectives, and to promote the exchanges occur from the experiences of participants and not from the responses of the coordinators. The coordination team (therapists and carriers) meets weekly and discusses relevant issues regarding the role facilitation. This space aims to empower carriers through the experiential process of coordinating the group, assuming the role of facilitators. Results: This action promotes the validation of the place of authority that the carrier itself has from his experience, making the protagonist and a multiplier of such an initiative. The group take as principle the collaborative dialogue and the themes to be discussed are spontaneously brought by participants. The profile of participants - is made up of both sexes, different ages and different stages of the disease, which contributes to greater diversification and enrichment of trade. The entry of patients in this group is through referrals made - by health professionals or through spontaneous (the group is disseminated through posters, website, or invitations to other participants). Currently the group has averaged 20 participants. Discussion: The Acolhimento Group contributes significantly to reduce the suffering of patients with schizophrenia, making it possible for better understanding of their disease and all that entails. In addition, through support, effective participation and collective construction of knowledge, raises up in participants a sense of belonging and helps to build a realistic hope towards life. It becomes possible to search by desires, interests and projects that may exist beyond the disease, providing the space for diversity and uniqueness. It facilitates the search for alternatives for a better quality of life and thus improve their social condition. Carriers are no longer patients but collaborators, becoming the protagonists of their projects not only therapeutic, but essentially their lives.

Randomized controlled trial with an educative intervention with participation of individuals with schizophrenia versus conventional classes to reduce stigma in medical students

Jorge C. Assis1, Elisa Brietzke1, Rodrigo A. Bressan1

1Programa de Esquizofrenia (PROESQ), Universidade Federal de São Paulo, São Paulo, SP, Brasil

Background: Stigma is a special relationship between one personal attribute and a negative stereotype. Empirical studies with interventions to reduce stigma are scarce, although this need in Psychiatry. The objective of this study is to compare the effect of an educative intervention with participation of individuals with schizophrenia with standard classes to reduce stigma in medical students. : One hundred thirteen medical students in the third year of the Federal University of São Paulo Medical School were divided in two groups using block randomization. One group received the studied intervention (class with participation of three individuals with schizophrenia) and the other received conventional class, with duration of four hours. The intervention included statements of three individuals (one with paranoid schizophrenia, one with schizo-affective disorder and one with refractory schizophrenia), that were trained in anti-stigma interventions followed by a section with questions and answers. Stigma was evaluated using the Students" Attitudes towards People with Schizophrenia Scale developed by Schulze, et al. (2003) and translated to Portuguese by Moraes (2006). The instrument is a set with 24 question whith the following options of answer: "agree", "disagree" and "I do not know". Results: Forty six students were submitted to the studied intervention and 67 to conventional classes. Both of groups were similar regarding sex (P = 0.263) and age (0.321). There were no statistically significant differences between percentages of answers "agree", "disagree" and "I do not know" between groups. Discussion: The results of this study did not support the efficacy of the intervention with individuals with schizophrenia in reduce stigma in medical students. Limitations of the instruments and the lack of evaluation before the intervention prevent definitive conclusions. In spite that, this is the first study involving individuals with schizophrenia in the training of medical students in Brazil. 

The role of the ombudsman at PROESQ - Schizophrenia Program of Unifesp (Federal University of São Paulo)

Jorge C. Assis1, Wagner B. Souza1, Lucas Bataglini1, Cecília C. Villares1, Rodrigo A. Bressan1
1Programa de Esquizofrenia (PROEQ), Universidade Federal de São Paulo, São Paulo, SP, Brasil
Background: The Schizophrenia Program (PROESQ) of São Paulo Federal University (UNIFESP) established in 2011 its Ombudsmanship. The initiative is a result of the process of empowerment and protagonism of its users and professionals, implemented in a consistent way through the years. Today, the ombudsman must understand the perspectives of the users and the perspectives of the team, and can exercise this responsibility, through dialogue and mediation, guided by actions validated by the service. It is expected that this initiative will contribute to PROESQ to accomplish its vocation of excellence in mental health in delivering assistance, teaching and research. The current ombudsman is a person with schizophrenia who was a user of the Program for two and a half years, and in 2008 was invited to integrate the team. He is supported by the service users, staff and coordinators to effectively consolidate the Ombudsmanship. : Application of the Satisfaction Scales of WHO − SATIS-BR, (Bandeira et al., 2000) with service users and staff, as a starting point to delineate aspects of activities of PROESQ that are relevant to the activities of the Ombudsmanship. For the application of the Satisfaction Scales SATIS-BR with service users, three users were trained as volunteer research collaborators. In addition to the survey, the Ombudsman will schedule individual appointments and a Suggestion Box will be available for written contributions. The professionals will be informed of the scope of activities of Ombudsmanship, to invite its utilization and to inform the users about the ombudsman practices. Results: The Ombudsmanship in the current phase is to disseminate new concepts between the users and professionals: through dialogic practices, contribute for the consolidation of the values of citizenship and to diffuse through the practical actions the concept that everyone can collaborate to improve the services received and given, as well as the activities developed at PROESQ. Discussion: The Ombudsmanship is an initiative that has developed together with the process of organizational restructuration of PROESQ, and it is directly linked to the Deliberative Council of the Program. It has the function of hearing and to the demands and internal suggestions. It also has the role to represent PROESQ in the matters related to advocacy, community issues, Public Power, and Law operators. This is a pioneering initiative in mental health in Brazil.

Using machine learning techniques to study discourse alterations in patients with schizophrenia

Álvaro Cabana1, Juan C. Valle-Lisboa1, Brita Elvevåg2, Eduardo Mizraji1

1Group of Cognitive Systems Modeling, Biophysical Section. Facultad de Ciencias, Universidad de la República, Montevideo, Uruguay/²Psychiatry Research Group, Department of Clinical Medicine, University of Tromsø, & Norwegian Centre for Integrated Care and Telemedicine (NST), University Hospital of North Norway, Tromsø, Norway


Background: The advent of computer programs that can process a large quantity of textual information affords the possibility of automatic analysis of speech from patients with psychosis. We have recently proposed that entropy measures, which assess discourse disorganization, can be employed to characterize speech samples from patients with schizophrenia. In particular, we wish to study how these novel language disorganization measures relate to illness severity. In order to measure entropy, automated methods able to assign different topic labels to speech samples are required. To solve this problem we adapt tools derived from the field of machine learning and evaluate the method using speech from patients and control participants. : Our approach is based on Latent Semantic Analysis (LSA), a method that creates a semantic space in which words are represented as points and the semantic relatedness of any two words is measured as the proximity of their representative points. An intermediate necessary step is to classify each piece of speech as belonging to a limited set of topics. In order to achieve this we post-process the LSA representation of each speech sample using Factor Analysis or Self Organizing Maps (SOMs). Then we measure the disorganization of speech using "topic entropy" and "transition entropy", which are measures that are sensitive to the level of topical disorganization of the discourse. Results: We apply these procedures to artificial examples and to real speech transcriptions. The artificial examples allow us to demonstrate that our methods accurately discover the underlying topics. Both SOMs and Factor Analysis are efficient at this task, although there are subtle differences when the output from these techniques are compared. Also, when applied to real speech transcriptions, the methods correctly assign the underlying topics in the majority of cases. This in turn allows us to measure topic disorganization using entropy measures. We find that considering only those cases where topic assignment is reliable, as expected the entropies are consistently higher in the discourse sampled from patients than in the discourse sampled from controls. Discussion: These methods promise to be a useful toolset to characterize the complexity in discourse in patients with schizophrenia. In particular, entropy measures summarize the underlying discourse disorganization. The next step is to model this disorganization with cognitive models, in particular using artificial neural networks.

Career guidance group with people with severe mental disorders: report of an experience

Beatriz Petreche1,2, Larissa C. Martini1,2, Fernanda A. Pimentel1,2, Fernanda V. Santos1,2, Dinara C. Souza1,2, Ana Olívia F. Silva1,2

1Programa de Esquizofrenia, São Paulo, SP, Brasil/2Universidade Federal de São Paulo, São Paulo, SP, Brasil

Background: The importance of having a job for patients with schizophrenia and other severe mental disorders is well established, however only a small percentage of this population have an employment. Studies show that to have a job has been associated with the improvement of their clinical state and social relationships, and also with the reduction of depressive symptoms. The restrictions to access a job are related to social and psychological barriers such as stigma of the employers and the self-stigma of the patients, and also to the lack of support and career guidance. The aim of this work is to report the experience of a career guidance group with patients with severe mental disorders under clinic treatment. : The main goals of the group are the insertion of the patients into the labor market, the identification and upgrade of their skills, assertiveness, job search, and the manner to deal with stress conditions related to the job. For that there were done 12 weekly meetings of one hour. During the first meeting there were registered the patient’s complaints, difficulties, and wishes, to be treated during the next meetings. After raising the main topics, a schedule was defined together with the group. The main topics approached were: social skills, assertiveness, stigma, job search, curriculum creation, and the growth of the social support network. The group was coordinated by a psychologist, an occupational therapist and a psychiatrist, including the members into the debates, working towards the growth of patients’ social relationships and gaining knowledge about their skills and problems. Results: It was verified with the group that the members could speak about their expectations in the regular job, as well as talk and clarify important aspects for individual work and group work. Besides they were stimulated to talk about the disease and the work. All patients had the opportunity to arrange their curriculum and think in more efficient ways to look for a job. Discussion: The group offered more security to patients on issues related to assertiveness and social relations, and facilitate the search for new job opportunities. Thus, it is understood that this strategy is essential to ensure the inclusion and maintenance of this patient's work.

Direct medical costs associated with schizophrenia relapses in three healthcare services in the city of São Paulo in 2006

Claudiane Salles Daltio1, Jair Jesus Mari1, Marcos Bosi Ferraz1

1Universidade Federal de São Paulo, São Paulo, SP, Brasil

Background: Significant cost is associated with schizophrenia and relapses are one significant cost element. The main objective of this survey is assess the direct medical costs associated with schizophrenia relapses at three mental health services in the city of São Paulo: a public state hospital (HP); a hospital affiliated with the Brazilian Unified Healthcare System - SUS (HCC); a Community Psychosocial Service Center (CAPS). : We reviewed the charts of 90 patients with schizophrenia who had been in services in 2006. We evaluated the resources used during the time these patients were in services. Results: The Mean Direct Medical Cost of schizophrenia relapses was, per patient, R$ 8.167,58 in HP; R$ 4.605,46 at the CAPS and R$ 2.397,74 in HCC (R$ 2/1 US$). The most significant component in all cases was the daily rate. The cost of medication differed depending on whether typical or atypical antipsychotics were used. CAPS making more use of atypical drugs. Discussion: The costs associated with schizophrenia relapses justify investments in antipsychotic drugs and strategies to reduce the need for mental health services, especially hospitals. The cost associated with treating patients in a CAPS is intermediate and has the added benefit of not depriving patients from their family life.

Psychiatrists´ stigma towards individuals with schizophrenia
Alexandre A. Loch1, Michael Hengartner2, Yuan-Pang Wang1, Wagner F. Gattaz1, Wulf Rössler2

1Departamento e Instituto de Psiquiatria, Faculdade de Medicina da Universidade de São Paulo, São Paulo, SP, Brasil/2Psychiatric University Hospital Zurich, Department of General and Social Psychiatry, Zurich, Switzerland

Background: Stigma towards individuals with mental illness can worsen the course and the outcome of the disorder. Studies show that anti-stigma campaigns should address specific populations such as the mental health professionals. However, literature on whether they stigmatize the individuals they treat is inconclusive. This study aims to evaluate stigma towards individuals with schizophrenia by analyzing a sample of psychiatrists frequenting the 2009 Brazilian Psychiatry Congress, considered the second largest psychiatric congress of the world.
: Out of the nearly 6,000 congress participants, 1,414 Brazilian psychiatrists were recruited to undergo the survey. Face-to-face interviews were conducted using a questionnaire that assessed stigma in three dimensions: stereotypes, social distance and prejudice related to someone with schizophrenia. Opinion on psychotropic drugs and tolerance to their side-effects were also assessed. Socio-demographic and professional data were collected. Results: Individuals with schizophrenia were more associated with negative stereotypes and less associated with positive stereotypes, when compared to someone of the general population. Stigma dimensions were weakly correlated. Negative stereotypes correlated with positive opinion on psychotropic drugs and with higher tolerance of side-effects. Higher age was correlated to positive stereotyping (OR of 1.91 for age > 50 years) and to less prejudice (OR of 0.47 for age > 50 years). Working at a psychiatric university hospital was protective against social distance (OR = 0.58). Discussion: Psychiatrists stereotyped negatively individuals with schizophrenia; analyses of other stigma dimensions and medication scales showed a possible resistance in revealing personal stigmatizing beliefs. Campaigns to promote self-awareness of these beliefs to fight stigma should be strengthened.

Brazilian version of the Independent Living Skills Survey (ILSS) with schizophrenic patients: cultural adaptation, reliability and validity

Larissa C. Martini1, Cecília Attux1, Rodrigo A. Bressan1, Jair J. Mari1,2

1Universidade Federal de São Paulo (Unifesp), São Paulo, SP, Brasil/2Institute of Psychiatry, King's College, London, United Kingdom

Background: There is a direct connection between good psychosocial functioning and the ability to carry out everyday tasks, preserve cognitive aspects and perform consistently well in the community. Despite the increase in the number of interventions focusing on independent living issues, most patients with schizophrenia still show significant limitations in this area. The aim of this study was to adapt and assess the reliability of the Brazilian version of the patient version of the Independent Living Skills Survey (ILSS) in patients with schizophrenia. : The reliability study of the Brazilian version of the ILSS was conducted with three different samples (one for inter-rater reliability test another for stability testing and the last one for the validation study) drawn from community mental health services in the city of Sao Paulo. Results: In the reliability study, fifty patients participated in the inter-rater study and 46 in the test-retest study. The inter-rater reliability coefficients showed a high agreement of 64.4% using Cohen's classification, and the Intra-Class Correlation values ranged from 0.80 to 0.99 for all subscales. The Intra Class correlation of the test-retest stability varied from 0.84 to 0.94, with 44.3% of perfect agreement according to Cohen´s classification. There was a good internal consistency. A hundred sixty patients were included in the validity study. In the discriminant validity study, female patients presented a higher performance in the global score and Appearance and Clothing (F = 6.243; df = 158; p = 0.014), Personal Hygiene (F = 10.273; df = 158; p = 0.002), Care of Personal Possessions (F = 12.732; df = 158; p = 0.000), Food Preparation (F = 8.784; df = 157; p = 0.004) and Transportation (F = 4.613; df = 157; p = 0.033) when compared with male´s performance. The concurrent validity confirmed the specificity of the scale dimensions, comparing ILSS with Positive and Negative Syndrome Scale - PANSS (r = -0.252, p = 0.001), Calgary Depression Scale (r = -0.185, p = 0.010), Global Clinical Impression - CGI (r = -0.409, p = 0.000), Global Assessment of Functioning - GAF (r = 0.477, p = 0.00), The World Health Organization Quality of Life - WHOQOL (r = 0.216, p = 0.006) and Rosemberg´s Self-Esteem Scale (r = 0.275, p = 0.000). Discussion: Everyday functioning measurements are becoming increasingly more necessary to complement evaluations of how schizophrenia impacts different areas of life, as well as to plan actions that can help rehabilitate and reintegrate patients into different social contexts. This is a broad study of the psychometric characteristics of the ILSS scale, and the main contribution it makes is providing the opportunity to use a survey with validity and legitimacy characteristics that are apt for the Brazilian context. 

Brazilian cultural adaptation of "Occupational Therapy Task Observation Scale" (OTTOS): application in patients with schizophrenia

Gabriela C. Moraes1,2, Fernanda V. Santos1,2, Rodrigo A. Bressan1,2

1Programa de Esquizofrenia, São Paulo, SP, Brasil/2Universidade Federal de São Paulo, São Paulo, SP, Brasil

Background: Nowadays, occupational therapy is broadly included among the mental health services offered, being one of the most privileged categories in mental care staff. The occupational therapist must grasp the demands and needs of the population. To this purpose, he or she usually employ evaluation instruments. According to their results, intervention projects take place. In different parts of the world, studies have been conducted to identify the effective measures and the objective assessments in respect of occupational therapy interventions about the individual's performance while carrying out his or her activities. In this scenario, the literature has presented specific instruments for a more accurate assessment of the patient thanks to occupational therapy. In Brazil, no instrument was found that specifically allows to evaluate the individual's performance. We believe that, for a complete occupational therapy evaluation of the patients, this stage is crucial. : Our main task was to use the US scale performance through cross-cultural validation to assess activities in occupational therapy. The instrument chosen was the 'Occupational Therapy Task Observation Scale' (Ottos), developed by Dr. Russell Margolis' team at the Johns Hopkins Hospital, and extended by Glenda Schnell, in New Zealand. It is an instrument used by the occupational therapist in charge for accompanying the individual, while doing activities, at the occupational therapy group. It takes one to two minutes to be completed, thus reducing the need for extensive narrative descriptions. Initially, the validation is conducted on a sample of schizophrenic patients. The validation methodology is composed of translation and back translation of the instrument, developing points of precision, checking the internal consistency and reliability of the scale, besides the criteria to validate it with other psychiatric and neuropsychological scales. Results: It appears that, after this study, one would be able to use the Occupational Therapy Task Observation Scale in the Brazilian population treatment, particularly with schizophrenic patients. This instrument allows a fast and objective reporting by the occupational therapist who, together with other members of a multidisciplinary team, provides a better understanding of the technical procedures used by the occupational therapists. Discussion: Brazilian validation of this instrument will contribute to occupational therapy all over the country. There are not many professional quantitative tools to assess their efficiency and effectiveness, especially in regard to the evaluation of patients while performing their activities.

Occupational Therapy in the Schizophrenia Program (PROESQ) of Sao Paulo Federal University (Unifesp)


Gabriela C. Moraes1,2, Larissa C. Martini1,2, Fernanda A. Pimentel1,2, Cecília C. Villares1,2

1Programa de Esquizofrenia, São Paulo, SP, Brasil/2Universidade Federal de São Paulo, São Paulo, SP, Brasil

Background: Schizophrenia is a multifactorial illness of chronic evolution characterized by alternating periods of crisis and stability. The complexity of the factors requires a complex treatment strategy, comprising a diversity of viewpoints and interventions on the same individual. The aim of Occupational Therapy is the carrying out of daily activities by the individual, to provide him with a sensation of pleasure and allowing him to keep his social activities. The majority of the patients directed to occupational therapy suffer from a considerable reduction of their social roles. On several occasions, they are qualified simply as ill persons or "schizophrenics". The other roles, such as father, mother, son, student, worker, friend, etc. are left aside or have not been practiced for a long time. The occupational therapist's first step is to make use of activities capable of wakening new interests and abilities in the individual, which not only develop and enlarge the occupational repertory but also open new ways of expressing, communicating and connecting feelings and/or emotions to words. One is to search practical daily activities of unique coherence for each individual. In the Schizophrenia Program of São Paulo Federal University (PROESQ/Unifesp) Occupational Therapy was included since the very beginning. Thereafter, several procedures were set up to improve the help provided to patients with schizophrenia. : The procedures currently applied through Occupational Therapy in the PROESQ/Unifesp program consist of individual appraisals, group attendance and working units coordination. Results: In the schizophrenia clinic, the occupational therapist makes use of several means to achieve the objective of a daily build up and social inclusion of his or her patients. Sometimes they are used all at the same time and other times step by step, depending on the therapist's evaluation of the patient's requirements and needs. Individual sessions are recommended for patients requiring private space for submitting their questions and elaborate on them. The patients requiring this type of treatment present most times a large wanting in their daily needs, requiring on the part of the therapist constant work to build up something which makes sense to them. The group attendance aims at developing their social connections, as well as providing an enlargement of their social network. For this intervention, the patients sent have some kind of restriction in their social network, and experiment difficulties in developing same because of the disease itself. The main purpose of the workshops is to provide grasps of life tied up to productivity and new shapes of social roles. In this area, the Occupational Therapy aims at linking the therapist to the work. Discussion: The work carried out by the Occupational Therapist at PROESQ/Unifesp is justified by its relevance in attending and treating the patients. The proposals have been constantly reviewed and constantly improved, to provide a better treatment to people with schizophrenia. Occupational Therapy has largely contributed to multidisciplinary discussions, amplifying the understanding of each patient's case, studying their situations in details, collecting information about their daily lives, their abilities, their capabilities and their wishes, with the purpose of matching the therapy case by case, according to very specific needs.

Mentally disturbed young individuals, living with their parents, in Sao Paulo, may experience a worsening of their condition, as a result of parental misconceptions of mental disease

Jose F. Quirino

Background: Scientific research has sufficiently established that external (cultural) factors influence the outcome of certain mental diseases in the individual, actually becoming a component of the disease. Among its mechanisms, one of importance is the parents' inappropriate rearing of young adults at home. This becomes apparent in at least two different processes: dealings between parents and their disturbed son (or daughter), and built-in barriers in the home intended to coerce the disturbed son. In consequence, mental disease at home may follow a particular course, inevitably detrimental to the disturbed individual. To investigate hidden contradiction in apparently well-meant parental behavior towards a son or daughter… a) as a direct parental attribution, and b) to identify spatial arrangements and furniture disposition in the home that can be, purposefully or not, interposed between parents and their mentally ill offspring. Research Question: Why do parents take a long time to seek medical help to a mentally disturbed son or daughter, and how spaces and furniture are manipulated in order to isolate the ill member in the home? : Qualitative data gathered includes in-depth open interviewing of the mentally disturbed and their parents, in 2 separate, complementary researches, as follows: a) research on the relationship among all residents and the ill person at home, and b) research on unusual uses of space and furniture in the home. The universe for researches a) and b) is the clientele of a public outpatient clinic operated by Unifesp's Departament of Psychiatry faculty. Sufficient interviewing sessions were made until non-conscious traits of behavior could be confidently detected and understood, leading to the underlying rationale for approaches a) and b). Results: Data of both researches a) and b) were compared, and a single recurring pattern was established: a) parents were found to delay their sons' attendance at the medical unit for some years because, for them, disturbance in behavior is not due to common disease, but rather to insanity, a state of mind resulting from a past pernicious episode, or from a demonic issue escaping medical action, as parents made clear when defining disease in terms of contagion or malformation, and adding that this is the characteristic field of medicine, not the lunacy of a son's possessed mind; b) the home of the mentally disturbed revealed the existence of mazes, and other forms of coercion, sometimes even aggression, (strong lighting with naked bulbs at the son`s room, "secure" corridors away from delicate furniture and machines) to physically separate and demean the presence of the mentally disturbed. Discussion: Misconception about mental disease is common in Sao Paulo households, being notably detrimental to disturbed young adults. It could, however, be dealt with In order to help medical care achieving a higher degree of effectiveness, if including appropriate counseling to all living under the same roof as the patient’s.

Dysfunctional family structure of children with bipolar disorder

Edmir Nader1, Ana Kleinman1, Bernardo C. Gomes1, Claudia Bruscagin2, Bernardo dos Santos3, Beny Lafer1, Sheila C. Caetano1

1Programa de Pesquisa em Transtorno Bipolar, Departamento de Psiquiatria, Faculdade de Medicina da Universidade de São Paulo, São Paulo, SP, Brasil/2Núcleo de Família e Comunidade, Pós-Graduação, Programa da Pontifícia Universidade Católica de São Paulo, São Paulo, SP, Brasil/3Universidade de São Paulo, São Paulo, SP, Brasil

Background: North-American studies have shown that Bipolar Disorder (BD) children's families environments, when compared to children and adolescents families with non-psychiatric disorders, were disorganized, presenting low cohesion among family members, high conflict levels and low maternal warmth. Furthermore, high expressed emotion (EE), that has been described in families with patients with Schizophrenia, has also been found in BD patient's relatives. Our aim was to compare BD children and adolescents' family structure with control families concerning family characteristics previously described as abnormal. Moreover, we intended to compare family structure of BD children and adolescents with psychotic features with families with non-psychotic BD patients. Hypotheses: BD children and adolescents' families compared to children and adolescents' families with non-psychiatric disorders would present: lower cohesion and maternal warmth, and higher levels of conflict and EE. Additionally, parents of psychotic BD children and adolescents would have higher EE than parents of non-psychotic BD patients. : Thirty two (32) families were selected after meeting the inclusion criteria: children between 6 and 18 years old with a DSM-IV BD diagnosis. Thirty (30) control families were selected: with children, adolescents and first-degree relatives with non- DSM-IV axis I psychiatric disorder. All children and adolescents were excluded if QI<70. Three scales were concurrently applied for this purpose: the Family Environment Scale (FES), the Psychosocial Schedule for School Age Children-Revised (PSS-R), and the EE Adjectives Checklist. Results: BD child and adolescent’s families when compared to families with non-psychiatric disorder, presented lower levels of cohesion (F = 13.62, p < 0.001), intellectual-cultural orientation (F = 4.79, p = 0.033) and organization (F = 12.55, p = 0.001) and higher levels of conflict (F = 23.76, p < 0.001) and control (F = 14.60, p < 0.001), according to the FES. BD child and adolescent’s families also presented lower levels of maternal (F = 16.78, p < 0.001) and paternal warmth (F = 8.34, p = 0.021), higher levels of maternal (F = 46.58, p < 0.001) and paternal tension (F = 25,67, p < 0,001) and a non-intact family (Wald = 7.859, p = 0.005), as per PSS-R. They presented as well lower positive EE (F = 58.54, p < 0.001), and higher negative EE (F = 103.52, p < 0.001) according to the EE Adjective Checklist. A Linear Discriminant Analysis was also carried out: negative EE (0.693) came in the first place, followed by positive EE (-0.533), maternal tension (0.457) and ranking fourth, paternal tension (0.390). Moreover, we did not find any difference between EE levels of parents of psychotic BD children (n = 14, mean age ± SD = 13.3 ± 3.8) compared with parents of non-psychotic BD (n = 18, mean age ± SD = 12.8 ± 2.6). Discussion: Family structures of BD children and adolescents present abnormal patterns related to communication and parents' tension.

The process of doing together: possibilities of therapeutic interventions in a recycled paper workshop with schizophrenia outpatients  

Juliana C. Pereira1,2, Pamela P. Pontes1,2, Larissa M. Campagna1,2, Fernanda V. Santos1,2, Cecilia C. Villares1,2, Thiago R. da Silva1,2

1Programa de Esquizofrenia, São Paulo, SP, Brasil/2Universidade Federal de São Paulo, São Paulo, SP, Brasil

Background: The Recycled Paper Workshop is one of the initiatives at the Hands in Art Project at the Schizophrenia Program
(PROESQ) of São Paulo Federal University (Unifesp). The workshop is constituted, at present, of five patients and an Occupational Therapy undergraduate intern, under the coordination of two occupational therapists. The workshop was created upon the request of relatives of patients attending the Program (PROESQ), that they developed some form of productive activity. The coordination changes every year after an adjustment period, in which the new therapists just observe the dynamics of the workshop. At our first contact, it was noted that the group had difficulties in performing in an autonomous way, and showed no ownership of space and material. Thus, we evaluated that the group was at a stage in which it required a closer approximation of the coordinators to the paper making process. The present paper aims to focus at the intervention of the coordinators, based on the process of ''doing together'' and the concept of empowerment. : Through case vignettes it will be presented the process that occurred in the first half of our coordination, when our goal was to work the needs and demands noted earlier. It was necessary a continued investment and support of the coordinators to make it easier for members to experience the technique and get in touch with the difficulties, offering evidence so that they could reflect on their production, their skills and autonomy within this space. Results: This movement enabled them to begin to understand important aspects of quality production and the resources needed to achieve results. Being closer to the patients in this process encouraged them to feel confident, creating, more horizontal relationships between them and the professionals that contributed to their empowerment process. Discussion: Thus, we believe that the process of "doing together" at this workshop is an instrument that has enabled the development of resources that increase independence and autonomy of the participants, leading them to increasingly take ownership of a physical and social space and allowing the construction and production which are both individual and collective.

Mosaic workshop: between production and therapeutic


Luanda Novais1,2, Anna Miranda1,2, Larissa M. Campagna1,2, Thiago R. Silva1,2, Cecilia C. Villares1,2, Fernanda V. Santos1,2

1Programa de Esquizofrenia, São Paulo, SP, Brasil/2Universidade Federal de São Paulo, São Paulo, SP, Brasil

Background: Psychosocial interventions aims to improve the remission the symptoms and preventing relapse, and to promote the functionality in areas such as independent living, interpersonal relationships and work. Some of the losses that schizophrenia may cause are related to the maintenance of work, interpersonal relationships and social life, and suffer the prejudice and stigma that exist in relation to disease. These limitations hinder the full participation in society of these carrier. From this fact, the Mão na Arte Project which is an initiative of Occupational Therapy Sector in Program de Esquizofrenia PROESQ/Unifesp -" EPM, aims to contribute to the social reintegration by work and sociability in patients with schizophrenia. The workshop mosaic is a member of this project, feature as a resource offered within the treatment. This space is proposed to be created as art or product that could be considered as symbolic means of social exchange and production of meaning. Nevertheless, this kind of work with patients is followed by some questions: how to correlate the therapeutic and production process in a way that will not impoverish relationships. Since production can be an obstacle to the establishment of interpersonal relationships, due to difficulties related to the participants interact. One example is the fact that participants stay focused on technique and do not undertake exchanges with other members about their production. : From this view, through an experience described by the coordinators of this workshop, the aim of this study is to discuss the work done in the workshop as an enabler for social and relational exchanges between participants, considering issues related to labor and production. Faced with the relational difficulties presented by members of the workshop, the coordinators have offered a new proposal, in addition to production. At the beginning of each meeting, participants were asked in a moment of discussion about the issues surrounding the workshop. The purpose was to make the participants perceive themselves and recognize themselves as members of the workshop. Results: Participants could express their difficulties, potentialities and how they establish their relations in this space. Discussion: These exchanges between the participants could move simultaneously to the creation and production. In this sense, the coordinators of the workshop could grasp this device as magnifier opportunities for discussion, dialogue, learning, living and as a means of creating significant changes in routine and daily life of these patients.

Culinary workshop: interaction between patients at healthcare staff

Flavia P. Camargo1,2, Thalita S. P. Rocha1,2, Fernanda V. Santos1,2, Larissa M. Campagna1,2, Thiago R. Silva1,2, Cecilia C. Villares1,2


1Programa de Esquizofrenia, São Paulo, SP, Brasil/2Universidade Federal de São Paulo, São Paulo, SP, Brasil

Background: The Culinary Workshop is a protected work initiative, primarily run by occupational therapists at the Schizophrenia Program (PROESQ) of São Paulo Federal University (Unifesp). The project aims at broadening issues related to job market and social reintegration, permeated by income generation. Workshop participants are Program patients who present a need to experiment work related situations connected with formal employment requirements. The culinary workshop is coordinated by two occupational therapists, along with a workshop technician. Initially the project was designed as an experimental group for testing recipes and discussion of the feasibility of marketing its products. With the development of the project the workshop became responsible for organizing and preparing coffee breaks at the weekly staff meetings and began to accept some outside jobs. With this expansion, and with the challenges generated by more responsibility involving activities, the workshop participants began to experiment a new relationship status with staff professionals. They started to act as service providers and to occupy a different place in social exchanges, not dominated only by their patient role. : This work aims to reflect about the changes in relationships between members of the workshop and staff members from the perspective of the coordinators of the workshop reported experience. Results: The project encouraged relationship status changes between professionals and patients. This is supported by the participants' perception of themselves as ''hired by'', and visualizing the professionals as ''contractors'' of their services. Participants gradually became more authoritative and demanding about their work, tolerating criticism as constructive, reflecting on the suggestions and developing more assertiveness towards new projects. These changes also respond to professionals who demand, notice, point out strengths and offer suggestions on products offered. Initially, staff members referred only to the professional coordinators, who sought to transfer responsibility to the participants, gradually helping them to own space and processes in this workshop. Discussion: In particular, this reflects the observation of professionals about the potentiality of the workshop's participants, of the services they offer, whether in the form of financial recognition or subjective appraisals. Another important result is the empowerment of the participants, as well as ownership of workshop processes, showing improved autonomy in the project.

Psychoeducation group for patients´ family members and schizophrenic patients

Eliana P. Guimarães1, Roseli L. Oliveira1, Wilze L. Bruscato2

1Centro de Atenção Integrada à Saúde Mental da Santa Casa de São Paulo, Serviço de Psicologia, Setor de Psicologia e Saúde Mental, São Paulo, SP, Brasil/2Irmandade da Santa Casa de Misericórdia de São Paulo, Serviço de Psicologia, São Paulo, SP, Brasil

Background: Schizophrenia is characterized by behavior patterns that cause severe impairment to the individual, family and community to which he belongs. The symptoms involve emotional, behavioral and cognitive dysfunctions, which lead to disruptions in social and emotional functioning. Psychoeducation provides greater patient adherence to treatment and contributes to the reduction of family burden, to the extent that the family will understand more about the disease and will be able manage the symptoms better. The objective for present research to describe a psychoeducational group intervention that aimed to guide patients and families about the disease symptoms and to improve treatment adherence. : Groups were conducted with patients’ family members and schizophrenic outpatients, hospitalized or in Day Hospital. Each group consisted of four sessions previously structured with specific questions related to the disease and its treatment, providing an opportunity to answer questions of the members. Results: After participating in a group, the family members were able to understand patients better and to help them in difficult situations. The patients were able to recognize the symptoms and they learned how to get the help they need, improving adherence to treatment. Discussion: The psychoeducational group intervention promotes exchanging of experiences, new coping strategies, more knowledge about the disease and its treatment, helping reducing relapses. Its main limitation is the engagement of patients and relatives.

Exercise of social group abilities for schizophrenic patients
Eliana P. Guimarães1, Roseli L. Oliveira1, Wilze L. Bruscato2

1Centro de Atenção Integrada à Saúde Mental da Santa Casa de São Paulo, Serviço de Psicologia, Setor de Psicologia e Saúde Mental, São Paulo, SP, Brasil/2Irmandade da Santa Casa de Misericórdia de São Paulo, Serviço de Psicologia, São Paulo, SP, Brasil

Background: Schizophrenia is characterized by behavioral patterns that lead to great commitment to the individual, family and community he/she belongs to. The symptoms involve cognitive, behavioral and emotional dysfunctions that lead to emotional and social losses. The Social Skills Exercise is defined as a series of techniques that seek to teach the individuals new abilities and keep them socially adequate, so as to allow for efficient social interactions. Group intervention may be a method to develop these abilities. The objective for present study to describe a group intervention that had improving the patients' quality of life, relationships and interpersonal communication as its main objective. : Groups of schizophrenic patients with negative symptoms in outpatient treatment. The activities were pre-established, with specific objectives, where things such as assertiveness, abilities to relate and other issued are worked on. The programme is made up of 10 120 minute structured sessions. Results: The programme has been used since 2002. It was possible to see a significant improvement in the participants' quality of life through the programme. They perfected their relationship with family, friends and in the professional scope. Discussion: The group sees the greatest number of people, providing the participants with interaction, who end up maintaining a bond even after the end of the programme. There is an exchange of experiences between participants and improvement in their autonomy. Another important factor is the limitation regarding patients' engagement, due to lack of involvement of family or patients' motivation, as a consequence to negative symptoms.

The effects of cognitive rehabilitation in executive functions of patients with schizophrenia: 5 years systematic review

Breno S. Vieira1, Bruno K. Schiavon1, Anelise M. Renner1, Rodrigo Grassi-Oliveira1

1Grupo de Pesquisa em Neurociência Cognitiva do Desenvolvimento, Programa de Pós-Graduação em Psicologia, Pontifícia Universidade Católica do Rio Grande do Sul, Porto Alegre, RS, Brasil

Background: Cognitive deficits in schizophrenia can limit social and vocational functioning even after treatment with currently available pharmacotherapies. Neurocognitive health could be understood as a protective factor to deterioration associate with psychopathology. Despite that there is not a gold standard treatment to cognitive decline in patients with schizophrenia. It is therefore important to evaluate new treatment approaches for these debilitating aspects of the illness. The main areas of cognitive deficits described in the literature include attention, executive function (EF), working memory, verbal memory, psychomotor coordination and learning ability. Moreover, many studies has been indicated an association between cognition and functioning. EF has been suggested as an important target that could help to improve functional outcomes.The aim of this study is to present a systematic review about the effects of cognitive rehabilitation in EF of patients diagnosed with schizophrenia. Since cognitive rehabilitation has shown efficacy in improving cognition in patients with schizophrenia. : English written published articles, published in the last 5 years, selection was performed in Medline, June 2011. The key terms used were "schizophrenia", "executive functions" and "rehabilitation". The search resulted in 12 articles that were systematically and independently examined by three investigators according exclusion criteria. As follow: a) no neuropsychological outcome as dependent variable b) articles without rehabilitation programs as independent variable and c) psychopharmacological efficacy studies. The authors also searched in the reference list. Our study attend the following steps analyzes design a) the methodological design b) sample size and characteristics (besides schizophrenia, schizoaffective disorder was accounted) c) the intervention used d) the independent variable e) the dependent variable and f) results. All these fields observed were utilized to the elaboration of a table exactly as described. Results: The most frequent cognitive training were Neurocognitive Enhancement Therapy (appearing 5 times), Work Therapy (appearing 2 times), Vocational Program (appearing 3 times), Standard Rehabilitation Program (appearing 2 times), Cognitive Remediation Therapy (appearing 4 times). All studies presented are clinical trials with the longest duration as 1 year follow-up. Just one study didn't find neuropsychological improvement after the intervention. There are differences between the time to restart daily activities after the treatment accordingly with the program chose. Discussion: The majority of articles found improvement of neurocognitive functions after cognitive training. Broadly EF has been proved to be predictive of social improvement in the context of rehabilitation.

Treating working memory deficits in patients with schizophrenia with repetitive transcranial magnetic stimulation


Mera S. Barr1, Faranak Farzan1, Melissa S. Daigle1, Lisa C. Tran1, Paul B. Fitzgerald2, Zafiris J. Daskalakis1

1Centre for Addiction and Mental Health, Toronto, Ontario, Canada/2Alfred Psychiatry Research Centre, Melbourne, Victoria, Australia

Background: Repetitive transcranial magnetic stimulation (rTMS) has the potential to improve working memory deficits in schizophrenia. The objective of this study was to examine the ability of rTMS to treat working memory deficits in patients with schizophrenia in a randomized, double-blind, placebo-controlled design. : Twenty-seven medicated patients with schizophrenia received either 20 Hz active or sham stimulation applied bilaterally over the dorsolateral prefrontal cortex (DLPFC) in 20 sessions over 4 weeks. Working memory performance was assessed prior to and following the rTMS treatment course using the verbal N-back task administered at 3 levels (1-, 2-, and 3-back). Results: Results revealed an approximate 10% increase in 3-back accuracy following active rTMS that was significantly different from sham (Cohen's d = 0.9). Discussion: These findings are the first to demonstrate improved working memory performance using rTMS in schizophrenia. Future studies are needed to replicate these findings and to also examine how rTMS may exert its therapeutic effects.

Cognitive remediation of patients with schizophrenia with an errorless learning method (Kumon method): a randomized placebo-controlled 

Marisa M. Crivelaro1, Paula A. Martins1, Silvia M. Arcuri1, Suely P. A. Ayuso1, Monia M. Musskopf1, Mario R. Louzã Neto1

1 Programa de Esquizofrenia (Projesq), Instituto de Psiquiatria, Hospital das Clínicas, Universidade de São Paulo, São Paulo, SP, Brasil


Background: Different techniques of cognitive remediation are used for the treatment of cognitive deficits in schizophrenia. In this study we want to test the efficacy of arithmetic calculations administered by the Kumon method (www.kumon.com.br) as cognitive remediation for patients with schizophrenia, in a randomized placebo controlled trial. The Kumon method is an individualized program of study and is planned according to the current capacity of the subject. Arithmetic exercises are offered in an ascending order of difficulty and the subject can only go to the next step when he/she could solve all exercises correctly. The subject solves all problems alone, after correction by the supervisor, if there are errors the sheet is returned to himself make the necessary correction without help of the supervisor. This procedure is repeated until all exercises are entirely correct. : The intended sample includes 50 subjects in the experimental group (Kumon) and 50 subjects in the control group (recreation), with the diagnosis of schizophrenia (DSM-IV-TR), of both genders, age between 18 and 55 years, with literacy. Both the experimental and the control groups attend a Kumon school twice a week for 50 minutes during 6 months (48 sessions). The experimental group attends the arithmetic classes administered by the Kumon method and the control group receives a nonspecific recreative intervention at the same place as the experimental group. At baseline, all subjects are evaluated with the PANSS (Positive and Negative Syndrome Scale) and the PSP (Personal and Social Performance) scales and with a neuropsychological battery. Our hypothesis is that arithmetic calculation training provided by the Kumon method reduces cognitive deficits in schizophrenia. The primary outcome is the neuropsychological composite score difference between baseline and after 6 months of training; secondary outcomes are psychopathological changes and social performance changes after 6 months. Patients will be followed up for further 6 months, without intervention to examine if the improvement persists at long term. Results: To date 91 patients were screened; 41 patients (32 male, 09 female), mean age 36.2 ± 8.6 years old, were randomized (10-block randomization). Of these, 19 attended the control group and 22 were included in the Kumon group. Until now, nine patients completed the first 6-month period of the trial and there were 6 dropouts. Both groups had similar scores on the neuropsychological tests, PANSS and PSP. As we have only 9 patients that completed the 6-month trial (3 Kumon, 6 control), we are not yet able to perform a statistical analysis to test our hypothesis. Discussion: This is an ongoing study. If our hypothesis is confirmed, the Kumon method has some advantages over other CRTs. It has a franchising system, with schools in almost all major cities in Brazil and other countries. It is highly systematized, and the structure of the arithmetic exercises begin with simple addictions and subtractions and goes until complex equations solving problems, thus simulating an errorless learning process like other cognitive remediation programs. It is relatively cheaper in comparison with CRTs applied by a trained psychologist. In a developing country where costs are an important limitation to care and patients have difficulty to access mental health services it might provide an alternative for cognitive rehabilitation of patients with schizophrenia.

Cognitive rehabilitation in schizophrenia: a souble-blind, randomized, controlled trial using simple resources

Livia M. Pontes1, Camila B. Martins1,2, Isabel C. Napolitano1, Juliana R. Fonseca3, Graca M. Oliveira1, Sandra M. Iso1, Anny K. Menezes1, Adriana D. Vizzotto1, Elaine S. di Sarno1, Marcelo Nogueira3, Helio Elkis1


1Programa de Esquizofrenia, Departamento e Instituto de Psiquiatria, Faculdade de Medicina da Universidade de São Paulo, São Paulo, SP, Brasil/2Instituto de Matemática e Estatística, Universidade de São Paulo, São Paulo, SP, Brasil/3Centro de Atenção Integrada de Saúde Mental, Hospital Santa Casa de Misericórdia de São Paulo, São Paulo, SP, Brasil


Background: Patients with schizophrenia can have prominent cognitive deficits, especially in attention, memory and executive functions. Although reports on cognitive training for schizophrenia have not been always uniformly positive, various studies showed positive results, indicating that it represents an effective treatment. As cognitive deficits are related to functional impairment and difficulty in keeping or finding jobs, the costs involved in this condition can become extremely high, thus emphasizing the importance of cognitive training. We performed a double-blind, randomized, placebo-controlled trial in order to investigate the efficacy of a low-cost attention and memory training program in a sample of stable Brazilian patients with schizophrenia. : Fifty-seven outpatients from two mental health units, from both genders, with ages between 18 and 50 years and who fulfilled DSM-IV-R criteria for schizophrenia were invited to participate in this trial. Subjects were screened based on the type of medication, history of neurological conditions, abuse or dependency of psychoactive substances, participation in a cognitive training program in the last six months, and were assessed for symptoms, I.Q, attention, memory and quality of life. Seventeen subjects comprised the final sample and were randomized in two groups: cognitive training or placebo training. Each intervention was composed of a total of 20 sessions, which took place along five months. Raters were blind to patients’ conditions, as well as the patients, who did not know to each group they were allocated. In order to compare groups on baseline, Mann-Whitney test was used to the continuous variables and qui-squared test was used to the categorical variables. A nonparametric repeated measures ANOVA was used for comparisons between groups in different moments (pre and post intervention). Results: The groups were comparable in terms of mental health unit to which they had been treated, gender, age, marital status, schooling, medication, disease duration, number of hospitalization and I.Q. Groups were also matched at baseline for symptoms, attention and memory measures, except for long term visual memory, which was superior in the experimental group. Some differences were also observed in quality of life, as the experimental group showed a more positive view of general health and psychological health. Final comparisons indicated that the cognitive training group showed a significant improvement in inhibitory control in comparison to the control group and a significant improvement in alternating attention over time. Both groups showed improvements in symptoms as measured by PANSS, information processing, selective attention, executive function and long-term visual memory. Improvements were found in the control group in long-term verbal memory and concentration in comparison to the experimental group. No differences were found in terms of the memory functional assessment or quality of life. Discussion: Our findings suggest that low-cost cognitive training in schizophrenia is feasible and may improve cognitive functioning and the inclusion of cognitive training interventions should be considered as a relevant therapeutic strategy in the treatment of schizophrenia.

CBT group intervention for schizophrenic patients
Eliana P. Guimarães1, Roseli L. Oliveira1, Wilze L. Bruscato2


1Centro de Atenção Integrada à Saúde Mental da Santa Casa de São Paulo, Serviço de Psicologia, Setor de Psicologia e Saúde Mental, São Paulo, SP, Brasil/2Irmandade da Santa Casa de Misericórdia de São Paulo, Serviço de Psicologia, São Paulo, SP, Brasil

Background: Schizophrenia is characterized by behavior patterns that cause severe impairment to the individual, family and community to which he belongs. The symptoms involve emotional, behavioral and cognitive dysfunctions, which lead to disruptions in social and emotional functioning. CBT is a psychological treatment approach that has showed good outcomes in treating these patients. Through specific techniques, the patients learn about their disease and how to cope with their symptoms which may help to better prognosis. The objective for the present study to describe a CBT group intervention for schizophrenic patients, this procedure aims to reduce the symptoms and their consequences, allowing individuals to have a better quality of life. : A group of schizophrenic outpatients, hospitalized or in Day Hospital, with a predominance of positive symptoms. This was an open group which sessions are semi-structured in advance, trying to work with current demands of each member. Results: The group has being going on since 2002. During the sessions, the patients have learned to cope better with the positive symptoms of the disease, dealing with delusions and hallucinations by means of behavioral and cognitive techniques. This helped them to develop social skills, providing healthier social interactions. Discussion: The CBT group intervention provides a number of models, helping the development of new behaviors and allowing benefit to a greater number of people. It also reduces positive and negative symptoms and relapses. Your main limitation is the engagement of patients who discontinue treatment due to lack of motivation, effort and patience.

Evaluation of the social skills inventory in patients with refractory and non-refractory schizophrenia: preliminary study

Silvia Scemes1, Bernardo dos Santos1, Mariangela G. Savoia1, Monica Kayo1, Helio Elkis1

1Instituto de Psiquiatria do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo, SP, Brasil

Background: It is well established that social skills are impaired in schizophrenia, especially in those most severe cases. The dimensions underlying the concept of social skills are complex and several methods of evaluation have been developed for its assessment. The Social Skills Inventory (SSI) was developed and validated in Brazil. The aim of the present study is to assess social skills in patients with schizophrenia using the SSI, comparing refractory and non-refractory subjects with normal controls obtained from the general population. : Outpatients with schizophrenia, either refractory or non-refractory, were recruited at the Schizophrenia Program of the Institute of Psychiatry, University of São Paulo General Hospital (Projesq-IPq). We included 33 patients with diagnosis of refractory schizophrenia and 29 non-refractory. Data from normal controls were provided by Del Prette, who developed the scale (Barreto et al., 1998). Means and standard deviation of SSI of the 3 groups were compared using one-way ANOVA based on the five factors obtained by a previous study (Barretto et al., 1998) through factor analysis. Post hoc Tukey multiple comparisons tests were used to assess differences between groups. Results: There was a significant difference between controls and patients, but no differences were observed between non-refractory and refractory groups, showing that both groups had similar impairment of social skills. We found a significant difference in Factor 3 (which evaluates mainly conversation social skills and social competence, reflecting self-confidence in affective neutral situations), between refractory patients and controls, reflecting a worsening of social competences in this domain. The F5 factor (ability to control auto aggressiveness, anger in case of aversive stimulation) had scores significantly higher in patients with schizophrenia, either refractory or non-refractory, in comparison with controls. Discussion: Our data showed a significant impairment of social skills in subjects with schizophrenia as measured by the SSI. The difference observed in F3 between controls and refractory patients might be due to the longer duration of illness, as the progression of negative symptoms has an impact on conversation skills, as refractory patients often live more isolated in the community. The fact that the factor F5 was significantly higher in patients with schizophrenia reflects the loss of ability to discern nonverbal cues, recognition of emotions through facial expressions, therefore not being able to realize when they are targets of jokes or criticism. SSI seems to be a useful assessment tool of social skills in schizophrenia, but could not detect significant differences between refractory and non refractory schizophrenia, which ins this case may be due to the small sample size.

Drug use associated to insight impairment in schizophrenic patients


Cátia Schmitt1, Karine Zortéa2, Juliana Gomes2, Maria I. Lobato2, Clarissa Gama2, Werner P. Knapp, Paulo S. Belmonte-de-Abreu2, Aaron T. Beck

1Hospital de Clínicas de Porto Alegre, Porto Alegre, RS, Brasil/2Universidade Federal do Rio Grande do Sul e Hospital de Clínicas de Porto Alegre, Porto Alegre, RS, Brasil


Background: Test the association between drug use (alcohol and cannabis) and insight measured by Beck Cognitive Insight Scale (BCIS) in patients with schizophrenia diagnosis. : Three-hundred and seven patients were included, most of them male, with the measurement of medical history, drug use, Psychopatology, Brief Psychiatric Rating Scale (BPRS), Insight (BCIS) and depression (Beck Depression Inventory (BDI). Insight was rated in specific categories (self-assurance e self-reflexivity). Results: There was a negative correlation between alcohol and cannabis use and total insight rated (p = .01). There was also a negative correlation between self-reflexivity and cannabis use (p = .01) and alcohol use (p = .03). self-assurance was associated to alcohol (p = .046) and failed to show correlation with cannabis use. Discussion: These results indicate that patients with comorbidity of schizophrenia and drug use, when compared to non-users, have reduced insight of own disease and its symptoms. Drug use affects not only their own perception, but also the ability to proper/successfull interpretation of attitudes of other people. These insight difficulties may contribute to reduced adherence to the treatment and handicaps in personal, social and family relationships. The health professional must be aware of negative consequences of drug use to work patient and family.

Insight assessment in patients with schizoaffective disorder, schizophrenia and its comorbidities

Cátia Schmitt1, Karine Zortéa2, Juliana Gomes2, Werner Paulo Knapp, Paulo S. Belmonte-de-Abreu2, Aaron T. Beck


1Hospital de Clínicas de Porto Alegre, Porto Alegre, RS, Brasil/2Universidade Federal do Rio Grande do Sul e Hospital de Clínicas de Porto Alegre, Porto Alegre, RS, Brasil

Background: Test the association between insight and schizophrenia subtypes and its comorbidities. : 310 subjects with DSM-IV diagnosis of schizophrenia were assessed at the three different clinics linked to Philadelphia university. Demographics data, clinical history, drug use, Brief Psychiatric Rating Scale (BPRS), Beck Cognitive Insight Scale (BCIS), and Beck Depression Inventory (BDI) were collected by trained interviewers. Patients were divided into 2 categories according to their diagnosis (schizoaffective and paranoid schizophrenia), and 2 cathegories according to comorbidities: with drug use, with other comorbidities. Results: There was no correlation among the analyzed categories in relation to the insight level. Paranoid schizophrenia showed later disease onset (p = <.01), and patients with comorbidities showed higher levels of depression on the BDI scale (p = .003). There was no association among other variables. Discussion: There was no difference in insight level measured by BCIS among diagnostic categories and comorbidity cathegories. Insights were not associated to schizophrenia compared to schizoaffective disorder. 

Patterns of antipsychotic prescription in community mental health centers in Sao Paulo - Brazil


Ana S. A. Silveira1, Deyvis M. L. V. Rocha1,2, Letícia A. Silva1, Camila Matsuzaka1, Claudiane S. Daltio1, Attux Cecília1, Rodrigo A. Bressan1,2

1Programa de Esquizofrenia (PROESQ), Universidade Federal de São Paulo, São Paulo, SP, Brasil/2Laboratório Interdisciplinar de Neuroimagem e Cognição LiNC, Universidade Federal de São Paulo, São Paulo, SP, Brasil

Background: The Psichosocial Care Centers (Centros de Atenção Psicossocial -" CAPS) are community based mental health services, held by Brazilian Unified Health System (SUS), for the treatment of people who suffer from severe mental disorders. The CAPS provide to their users intensive, multidisciplinary and community care, focusing on the medical treatment and the social reinsertion of the patients through access to work, civil rights and leisure. In our country, they serve as a substitutive for hospitalizations. Since the beginning of the 2000's, the CAPS have been the main strategy of mental health policies for health care delivery to out-patients with schizophrenia and related disorders. Though the CAPS have their focus in rehabilitation, they are also responsible for others clinical interventions, with regard to the prescription and the administration of medications. This study aimed to identify the profile of antipsychotic prescription in the CAPS in the city of São Paulo-Brazil. : A retrospective study was run in six CAPS of São Paulo. We started by selecting, through a chart review in each center, all the cases where a diagnostic of schizophrenia or other psychosis (ICD F20 to F29) were recorded. The patterns of antipsychotic prescription were registered. Then, a screening questionnaire was given to the psychiatrists of each center so they identify levels of antipsychotic adherence for all their patients: 1. No adherence, 2. Unsatisfactory adherence, 3. Satisfactory adherence, and 4. Total adherence. Results: Until now, 12 psychiatrists were interviewed in four different CAPS. 430 patients had diagnoses ranging from F20 to F29. Sixty-one percent of the patients were, by the time of the study, on antipsychotic monotherapy, 37,9% were on politherapy and 1.1% were not taking antipsychotics. Thirty-seven point seven of patients were taking atypical antipsychotic as monotherapy, 19.3%, oral typical monotherapy and 10.0% were on monotherapy with long action typical antipsychotic. Concerning treatment adherence, psychiatrists considered that 77.7% of their patients took all doses prescribed, 16.5% did not take all the doses prescribed, but their adherence were considered satisfactory, 5.3% took an unsatisfactory amount of the antipsychotic doses and 5.0% of the patients took no medication at all. The most used antipsychotic was haloperidol (39.1%) and haloperidol decanoate (31.2%), followed by olanzapine and chlorpromazine (26.6%), risperidone (14.1%) and quetiapine (10.2%). Only 4.8% use clozapine, although the evidences suggest that around 30% of schizophrenic patients are resistance to treatment and at least part of this population would benefit from the use of clozapine. More results will be available by the Congress. Discussion: We found that the typical antipsychotic haloperidol was the most prescribed treatment for the patients in the CAPS. Its long action formulation, used mostly in cases of non-adherence to treatment, was used in 31.2% of patients, although the psychiatrists considered that only 10.3% of all patients had an unsatisfactory adherence or did not take any dose prescribed. Although with no scientific evidence, there was a high number of antipsychotic politherapy prescription, meanwhile the total of clozapine prescription (4.8%) is far below the expected for the total of patients with treatment-resistant schizophrenia or related disorders (around 30%).

Parametric evaluation of a sensorimotor filter model for the study of schizophrenia


Michelle Brosco1, Nicole Henriques-Santos1, Gabriela Tunes1, Cristiane Salum1


1Universidade Federal do ABC, Centro de Matemática, Computação e Cognição, Santo André, SP, Brasil

Background: Prepulse inhibition (PPI) is widely used model to study psychiatric disorders, like schizophrenia given it evaluates the sensorimotor filter which is deficient in this disease. PPI is the reduction in amplitude of startle response (ASR) to an intense auditory stimulus (pulse, P) when it is preceded by a stimulus of low intensity (pre-pulse, PP). There is great variability in the PPI according to the parameters and configuration of equipment used in tests on rodents and humans. Schizophrenic patients and normal volunteers or rodents treated with dopaminergic agonists or glutamatergic antagonists present significant reduction on PPI. Among the factors that influence PPI are: the ratio of background noise/stimuli (stimulus salience), the interval between stimuli presentations and the intensity and duration of stimuli. This study evaluated the following hypotheses: i) the pulse intensity influences the percentage of PPI, ii) the intensity of background noise influences the percentage of PPI, iii) the stimuli interval between influences the percentage of PPI. 
: Male Wistar rats (180-400 g) were tested individually in each startle boxes (INSIGHT) with the following protocol: five minutes of acclimatization (background noise - BN only), then they received 10 presentations of P (white noise, 40 ms) and the PPI test, consisting of pseudorandom presentation of stimuli 64: P, PP (pure tone, 3 kHz, 69, 73 and 81 dB, 20 ms), PP + P (100 ms between stimuli) and null (no stimuli). Experiment 1: Pulse intensity varied on 100, 110 and 120 dB with BN of 60 dB and interval of 15 s; Experiment 2: BN varied on 57, 60 and 65 dB and P of 110 dB; Experiment 3: intervals varied from 15 and 30 s with BN of 65 dB and pulse 100 dB or and BN of 60 dB and P of 110 dB. The percentage of PPI was calculated as follows: % PPI = 100 - (100 * PP + P / P) in three levels of PP. Results: Experiment 1: repeated measures ANOVA of %PPI with pulse and intensity of PP factors showed a significant overall effect of the pulse and intensity of the PP test (P < 0,001; F[2,54]= 21,496) (n = 24), and the %PPI in the intensity of 120 dB were higher in the intensities of 69 dB and 81 PP (P = 0,05). Experiment 2: repeated measures ANOVA of % PPI with the background noise and intensity factors showed a significant overall effect of background noise (P < 0,001; F[2,94]= 60,903) (n = 20), whereas the intensity of 60 dB of BN was the one with the lower % PPI (P = 0,05). Experiment 3: repeated measures ANOVA of % PPI with the interval and intensity factors had no significant effect of interval (n = 10 - 24), no interaction between the factors. Discussion: The results presented here demonstrate the importance of setting parameters for better % PPI. The present study corroborates previous works showing that background noise influences the processing of prepulse which may be used to explain the deficiency that schizophrenic patients have in sensorimotor filter. Moreover, the pulse intensity was shown to influence PPI what can be explained as a higher salience of the stimulus related to the background noise, that is, the signal-to-noise ratio. More studies are needed in order to find out the specific influence of each parameter on PPI and on schizophrenic deficiency in PPI.  

Spiking network models of schizophrenia: a review

Thiago Borduqui1,2, Antonio C. Roque1, Jaime E. C. Hallak1

1Universidade de São Paulo, Ribeirão Preto, SP, Brasil/2Universidade Católica de Brasília, Brasília, DF, Brasil

Background: Computational neuroscience is a branch of theoretical neuroscience that deals with plausible biological computational models. This kind of model is based on empirical findings that come from different brain study approaches and may incorporate neuron electrophysiology, synaptic dynamics, long term potentiation and depression, local and global architecture connections. Recent studies have introduced schizophrenic aspects in spiking network models (special kind of neural network that accounts for the precise spike-timing nature of neural processing), and they have demonstrated theoretically the biological substrate of negative, positive and cognitive symptoms. : A search was made in the PubMed database, its last access being in May 2011, using the keywords "computational", "neurocomputational", "neural network", "attractor network", "Spiking network" and "dynamical systems", all of them together with "schizophrenia". Twelve studies that deal with spiking network models of schizophrenia were selected. Results: The main theoretical findings are: (i) decrease in the NMDA (Nmethyl-d-aspartate) receptor conductance in the pre-frontal cortex (present in schizophrenia), which underlies short-term memory and attention, reduces the depth of persistent basins of attraction, i.e. those states related to high firing rates, causing short term memory instabilities, usually linked to cognitive symptoms of patients; (ii) decrease in the inhibitory GABAergic (gamma -" aminobutyric acid) currents (present in schizophrenia) reduces the depth of both spontaneous and persistent basins of attraction, causing instability that allows thoughts to jump to both attractors, even in the absence of stimuli, a phenomenon that is associated to positive symptoms of schizophrenia; (iii) negative symptoms are related to decreases in firing rate (as in the orbitofrontal cortex and/or anterior cingulate cortex of schizophrenic patients) and to shallower basins of attraction; (iv) alterations in dopamine modulation influence the signal-to-noise ratio, which can be seen as working memory deficits (present in schizophrenia); (v) decrease in grey matter volume, which occurs at the time of late adolescence, may contribute to the onset in some individuals of schizophrenia at this time. Discussion: In our point of view, spiking network models can contribute to schizophrenia research providing a mathematical framework for studying underlying mechanisms involved in some brain functions. The models have become increasingly sophisticated and they help to understand the diminished stability and noisy dynamical behavior of prefrontal cortex networks in schizophrenia. Important results, consensual in the literature on schizophrenia, could be confirmed. Hypotheses (as the unification of working memory, attention and decision making in a single neuronal substrate) could be tested and we believe that predictions can be made. We criticize the fact that the vast majority of the implementations were based on the recurrent integrate-and-fire network model. We believe that more realistic models should be used to confirm these findings.

Early frontotemporal dementia or vesanic dementia? A case report of a “schizophrenic” patient who developed dementia

Daniela L. R. Taveira1, Roberto B. R. Taveira2, Leonardo F. Caixeta2, Cláudio H. R. Reimer1, Ciro M. Vargas1, Alexandre A. C. Peleja2

1Pontifícia Universidade Católica de Goiás, Goiânia, GO, Brasil/2Universidade Federal de Goiás, Goiânia, GO, Brasil

Background: Vesanic dementia, a term of French origin of the nineteenth century referred to the psychiatric diseases that evolved with dementia. With the changes in psychiatric nosological classification, the term was abandoned and the term schizophrenia was considered a dementia by Kraepelin. The Frontotemporal Dementia (FTD) spectrum includes social and behavioral changes, cognitive deficits and motor dysfunction. : Case report based on psychiatric history, psychiatric examination (including Mental Status Mini-Examination (MSME)), neurological examination and Computer Brain Tomography (CCT). Results: A seventy-year-old retired woman had a history of mental disorder since the age of 33 when he started having persecutory delusions. Due to hetero-aggressiveness, she was admitted in hospital for the first time, receiving a diagnosis of schizophrenia. Since then, she started to use first-generation antipsychotics, never fully returning to what she was like before. She became increasingly dysfunctional, impulsive and self-neglect, with low hygiene and wandering. From 40 years onwards, several hospitalizations ensued. The patient developed seizures (tonic-clonic). Around age of 50 she began to complain of hypomnesis. Over the past five years she showed worsening of memory, sometimes getting lost in the street and “forgetting” how to cook. The speech became poorer and concreter, and in recent months, her behavior expressed extreme aggression (in the context of persecution), associated with intense apathy, hypobulia and initial insomnia. Psychic exam showed low hygiene, she was disorientated temporally and spatially, with slowed thinking, poor and concrete speech, with delusional ideation and transient persecutory delirious with false recognition, hypobulic, presenting stammering and mild dysarthria. MSME: 15 points. CBT showed bilateral frontotemporal atrophy with temporal predominance. Discussion: Cognitive impairments are recognized as a possible symptomatologic axis in the clinical complexity of Schizophrenia. Dementia is not considered a consequence of schizophrenia, but a distinct pathological process, which leads to a reflection (and confusion) on the diagnosis and physiopathology involved. In our case there are questions about the real source of cognitive degeneration; would it result from Schizophrenia (regaining the diagnosis of Vesanic dementia), or due to possible FTD early-onset? Judging by the neuroimage, we tend to think in the framework of FTD. When we analyze the history of the pathology, we conclude it is a FTD, with the characteristics behavior changes, cognitive impairments (especially the speech disorder) and motor deficit. In addition, some patients with early FTD onset may present clinical disorders with initial psychotic symptoms and may be initially diagnosed with schizophrenia, and only years later, receive the diagnosis of FTD due to cognitive changes. Such fact leads to more confusion and misdiagnosis as schizophrenia and early onset FTD may present with similar symptoms, since the involvement of cerebral sites are shared by the two diseases.

Psychotic symptoms in the elderly: prevalence in Alzheimer's disease and nondemented individuals from a community-based sample in Brazil

Salma R. I. Ribeiz1, Debora P. Bassitt1, Julio Litvoc2, Cassio M. C. Bottino1


1Instituto e Departamento de Psiquiatria, Universidade de São Paulo, São Paulo, SP, Brasil/2Departamento de Medicina Preventiva, Universidade de São Paulo, São Paulo, SP, Brasil


Background: Psychotic symptoms are reported to be uncommon in the elderly, and may be underrated in traditional epidemiological studies. The aim of this study is to estimate the prevalence of psychotic symptoms in old age individuals with Alzheimer Disease (AD) and nondemented from a community-based sample from Sao Paulo, Brazil. : An epidemiologic survey was made in Sao Paulo with 1,563 persons over 60 years old, stratified according to economical status. They were evaluated with MMSE, FOME, IQCODE, B-ADL, a sociodemographic, clinical and socioeconomic inventory and three questions about psychotic symptoms extracted from CAMDEX. Screen positives were submitted to a workup for dementia, physical and neurologic examination, the CAMDEX, CDR, and NPI. Diagnosis was made according to Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition criteria. Individuals were divided in two groups: Alzheimer Disease (AD) and nondemented elderly. Results: Descriptive analysis (crosstabs and Chi-square test) showed that 10.1% of the nondemented group answered that they have heard voices and 21% of the AD group confirmed that they have heard voices (p < 0.05). Paranoid ideation was confirmed for 4.2% of the nondemented group and for 10.4% of the AD group (p < 0.05).Visual hallucinations were reported by 10.3% of the nondemented group, while 15.9% of the AD group reported these symptoms (p = 0.07). Discussion: Psychotic symptoms are more prevalent in Alzheimer disease than in nondemented individuals in this community-based sample. However, a sizeable frequency of nondemented elderly reported psychotic symptoms. Longitudinal studies are required to elucidate if the presence of psychotic symptoms may be a predictive symptom of dementia in the future.

BDNF and inflammatory cytokines in depression in schizophrenia


Cristiano Noto1, Ary Gadelha1, Elisa Brietzke2, Síntia I. Belangeiro3, Clarissa S. Gama4, Rodrigo A. Bressan1,2


1Programa de Esquizofrenia, Departamento de Psiquiatria, Universidade Federal de São Paulo, São Paulo, SP, Brasil/2Programa de Intervenção em Indivíduos em Risco de Estado Mental, Departamento de Psiquiatria, Universidade Federal de São Paulo, São Paulo, SP, Brasil/3Departamento de Genética e Morfologia, Universidade Federal São Paulo, São Paulo, SP, Brasil/4Laboratório de Psiquiatria Molecular, Hospital de Clínicas de Porto Alegre, Porto Alegre, RS, Brasil

Background: Involvement of inflammatory processes in the pathophysiology of psychiatric disorders has been suggested. Cytokines have received special attention as potential mediators of the interaction between immune and neuroendocrine systems. Previous reports have suggested a proinflammatory state associated with Schizophrenia, where it is involved in complex and reciprocal interactions with neurotrophins, such as BDNF. : Forty seven individuals (83.8% male; 16.2% female) with diagnosis of schizophrenia according DSM-IV were included (mean age 34.46; SD = 11.48). Psychotic symptoms severity was evaluated by Positive and Negative Symptoms Scale (PANSS) and severity of depressive symptoms was evaluated using Calgary Depression Scale for Schizophrenia (CDSS). Acute or chronic general medical conditions associated with imbalances in inflammatory response were considered an exclusion criterion. Blood samples were withdrawn for measures of BDNF and inflammatory cytokines (IL-1beta, IL-6, IL-8, Il-10, IL-12 and TNF-alpha). BDNF was measured trough BDNF levels were measured with ELISA, using a commercial kit according to the manufacturer's instructions (Chemicon, USA). Cytokines were determined by flow cytometry (BD Biosciences, USA). Results: All the patients were in current psychopharmacological treatment and mean scores in PANSS and in CDSS were 64.14 and 3.57 scores. A correlation between PANSS and CDSS was not found. IL-1beta presented a positive correlation with total PANSS score (correlation coefficient = 0.374; P = 0.023). In addition, BDNF presented a positive correlation with CDSS (correlation coefficient = 0.464; P = 0.004). Discussion: The positive correlation between BDNF and CDSS found by us helps to support the evidence of high levels of BDNF as a compensation mechanism for inflammatory damage and consequent metabolic stress; at least, in this cohort of chronically medicated patients with schizophrenia. In addition, this opens a venue for investigation on the role of neurotrophins in neurotoxicity pathway in the course of SZ.

The natural history of depressive symptoms in schizophrenia: a cohort study

Antonio R. Sa1, Belquiz S. Avrichir1, Helio Elkis1
1Programa de Esquizofrenia, Departamento e Instituto de Psiquiatria, Faculdade de Medicina da Universidade de São Paulo, São Paulo, SP, Brasil
Background: Depression is common in people with schizophrenia and is associated with substantial problems including more frequent relapses, an increased risk of suicide, quite an unfavorable outcome and an increased duration of illness. To evaluate the natural history of depressive symptoms in schizophrenia and the effects of atypical or typical antipsychotics in depressive symptoms we conducted a prospective cohort study of patients with schizophrenia treated with typical and atypical antipsychotics. : The data were drawn from a retrospective, naturalistic, observational cohort study with 96 subjects diagnosed as being affected by schizophrenia according to the DSM IV-TR, during a re-exacerbation phase. The patients were taking typical or atypical antipsychotics. All subjects completed the Calgary Depression Scale for Schizophrenia (CDSS) to rate the severity of the depressive symptoms. The severity of schizophrenic symptoms was rated by the Positive and Negative Syndrome Scale (PANSS) and the Clinical Global Impression (CGI) severity and improvement scales. Assessments of scales above were undertaken at baseline, 8 weeks, 16 weeks and 24 weeks. Results: Improvement of depressive symptoms was associated with use of antipsychotics, but the improvement was statistically significant just with atypical antipsychotics. The PANSS total score higher than 70 and female gender were significantly associated with the presence of depressive symptoms. Discussion: Our findings suggest that atypical antipsychotics seem to be more effective on the depressive symptoms during the course of schizophrenia than typical antipsychotics according with assessment by CDSS and PANSS depressive items. The factors that seemed to affect the presence of depressive symptoms were gender (female) and higher severity of schizophrenia, information that should make clinicians especially attentive while taking care of these patients.

Thought and language disorders in young patients with schizophrenia or bipolar disorder
Telma Pantano1, Lee Fu I1, Eliana Curatolo1, Camila B. Martins2, Helio Elkis1
1Departamento e Instituto de Psiquiatria, Faculdade de Medicina da Universidade de São Paulo, São Paulo, SP, Brasil/2Instituto de Matemática e Estatística, Universidade de São Paulo, São Paulo, SP, Brasil
Background: Thought and language disorders (TLD) are considered one of the main psychopathological features of schizophrenia or schizoaffective disorder and may represent a hallmark of the disorder but such abnormalities are also present in adult patients with bipolar disorder, although considered less severe than those found in schizophrenia. Various studies compared adult patients with schizophrenia or schizoaffective disorder with bipolar patients but the investigation of such abnormalities in young patients is scanty. Therefore the aim of the present study is to assess TLD comparing young patients with diagnosis of schizophrenia (SCZ), schizoaffective disorders (SCA) and bipolar disorders (BD). : Forty-one patients with exacerbation of psychotic symptoms (18 with diagnosis of the SCZ, 16 with BD and 7 with SCA with aged between 10 and 17 years old at the time of the initial treatment as well as for language and cognition evaluation). The subjects were recruited for treatment at the outpatient clinic of the Child and Adolescent Unit of the Institute of Psychiatry of the University of Sao Paulo (IPq) in Sao Paulo, Brazil and completed a series of neurocognitive and psycholinguistic tests, including the Thought, Language and Communication Scale (TLC). Results: Performance tests which measured thought, language and cognitive abnormalities showed a consistent difference between groups (p < 0.05) regarding the following variables: semantic, syntactic, digit spam, metaphors comprehension and TLC scale. There were no significant differences (p < 0.05) in terms of performance between the groups regarding the function executive tests as well as the time processing. The SCZ group performed worse in all the TLC tests, followed by SCA and BD groups, with the latter exhibiting the best general performance. Such results reinforces the notion of the a continuum of psychoses since, in terms of severity, patients with SCZ showed the worst performance, patients with BPD the best performance and those with SCA occupied in intermediate position. The relationship between total thought disorder and other variables were further examined using multiple regressions. The metaphor's test (t = -5.338; p = 0.000) emerged as the best predictor of the TLC scale in all the groups, with patient with SCZ showing the worst results in such test. Discussion: To our knowledge this is the first study to compare young patients with SCZ, SCA and BPD in terms of the TLD, using the TLC. Additionally the study showed, as compared with the other groups, patients with SCZ had the worst performance especially in terms of the semantic and syntactic tests, general cognitive tests, executive functions, as well as the metaphor test, which was identified as the best predictors of thought disorder.

The argument structure of the discourse of a patient with schizophrenia: a linguistic analysis

Marcus L. Gomes1
1Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brasil
Background: The presence of changes in language in patients with schizophrenia and its importance to the diagnostic process is present since Kraepelin (1919) and Bleuler (1911) to the latest diagnostic classifications like the DSM-IV and ICD-10. A review of recent literature on the subject shows evidence of changes in the pragmatic level of understanding and language production in patients with schizophrenia, as well as measurable changes in linguistic structures. (Delise, 2001; Morice and Don McNicol, 1986; Chaika and Lambe, 1986; Harrod, 1986). This study is based on the theoretical framework of Cognitive Linguistics and its premise that the use of linguistic forms is intrinsically related to cognitive processes. One can therefore expect that psychopathological conditions show changes in language production and study of such changes may contribute to the comprehension of language processing, as for the understanding of psychopathology. In general, the concepts of Cognitive Linguistics have collaborated to several researchs in psychology and psychiatry, showing that the investigation of linguistic phenomena, from this perspective, may have great relevance to other areas of knowledge aswell. : This study starts from the hypothesis presented in Radden and Dirven (2007) that there is a relationship between a conceptual core of a situation (understood as the relationship between two or more conceptual entities) and its expression in grammatical constructions. Thus, the different event schemas are expressed in the language by different grammatical patterns that have specific constituents and syntactic functions. This study examines, then, the thematic distribution of clause-related units present within the discourse of a patient with schizophrenia, trying to define general cognitive schemata related to the semantics and argument structure. Results: Partial results of this research shows that it is possible to describe specific schematic relations between different conceptual entities present in the discourse of a patient with schizophrenia, based on the thematic distribution of clause-related units. In this case, conceptual entities central to delirium in the speech of such a patient are primarily decoded into certain thematic patterns and arguments that reveals specific conceptual relations. In the related corpus, the thematic distribution of agent (antagonist)/patient, and their respective argument structure, was the main pattern used to describing certain delusional aspect. This point to a relationship between the delusional event and sentential patterns that is not completely arbitrary. Discussion: The present study indicates that a linguistic analysis can contribute to design aspects of cognitive organization of these patients and to collaborate in the diagnostic process. Cognitive linguistics has moved towards developing a methodology, based primarily on language in use, connected to the study of cognitive and subjective phenomena. In this sense, it has the potential to assist in the development of new methodologies for the studies in psychiatry and psychology. The linguistic description of psychopathological phenomena, as well as the presence of measurable standards syntactic and semantic speech in patients with schizophrenia, as described in this paper offers a new model for research in psychiatry and psychology and has the potential to provide new tools for definition of criteria for the differential diagnosis process.

Executive functions structure in schizophrenia patients: a latent variable analysis
Arthur Berberian1,2,3, Bruno S. Scarpato1,2,3, Acioly T. Lacerda1,2,3, Rodrigo Bressan1,2,3
1Laboratório Interdisciplinar de Neuroimagem e Cognição (LiNC), Universidade Federal de São Paulo, São Paulo, SP, Brasil/2Programa de Esquizofrenia (PROESQ), Departamento de Psiquiatria, Universidade Federal de São Paulo, São Paulo, SP, Brasil/3Departamento de Psiquiatria, Universidade Federal de São Paulo, São Paulo, SP, Brasil
Background: Executive deficits have been consistently reported in schizophrenia, which have also been associated with poor functional outcomes and with treatment refractoriness. However, there is still a debate over the exact nature and pattern of selective differential deficits relative to a more general executive impairment in patients with schizophrenia. We used confirmatory factor analysis (CFA) to verify the latent structure of three EF subdomains - mental set shifting, information updating and monitoring, and inhibition of prepotent responses - and their roles in complex executive tasks, in order to understand how EF are organized and what roles they play in complex cognition in schizophrenia. If this model is supported, it might lead the field to draw different conclusions about how cognitive functioning relates to functional outcome as well as about rational treatment design and testing. : Executive deficits have been consistently reported in schizophrenia, which have also been associated with poor functional outcomes and with treatment refractoriness. However, there is still a debate over the exact nature and pattern of selective differential deficits relative to a more general executive impairment in patients with schizophrenia. We used confirmatory factor analysis (CFA) to verify the latent structure of three EF subdomains - mental set shifting, information updating and monitoring, and inhibition of prepotent responses - and their roles in complex executive tasks, in order to understand how EF are organized and what roles they play in complex cognition in schizophrenia. If this model is supported, it might lead the field to draw different conclusions about how cognitive functioning relates to functional outcome as well as about rational treatment design and testing. Results: The Goodness-of-Fit Index (GFI) was 0.98 and the Root Mean Square Error of Approximation (RMSEA) was 0.04 suggesting a good overall fit to data. Shifting factor presented high correlation with Inhibition and Updating. Inhibition presented moderate relationship with Updating. Inhibition followed by Shifting, were the factors that most explained TOL and WCST performance. Discussion: Cognitive dysfunction may account for 20% to 60% of the variance in functional outcome in schizophrenia, and the need to identify specific mechanisms and components is relevant because each aspect may have different implications in the behavior. This model suggests that EF in schizophrenia exhibit three intercorrelated but independent dimensions. Inhibition was the dimension that most influenced complex executive tasks, followed by Shifting. Present findings might have important implications in both neuropsychological testing and treatment.

Cognition and facial affect processing in treatment-resistant schizophrenia patients and first-degree relatives

João Paulo Machado-de-Sousa1,2, Cristiano Chaves1,2, Carlos Barros e Silva1, José A. Crippa1,2, Nelson Torro3, Márcio
Tiradentes1, Jaime E. C. Hallak1,2


1Departamento de Neurociências e Ciências do Comportamento, Ribeirão Preto, SP, Brasil/2Instituto Nacional de Ciência e Tecnologia Translacional em Medicina -" CNPq, Ribeirão Preto, SP, Brasil/3Universidade Federal da Paraíba, João Pessoa, PB, Brasil

Background: Schizophrenia is associated with progressive cognitive deterioration and poor social outcome, believed to be associated with impaired processing of environmental emotional cues. Between 20%-30% of schizophrenia patients do not respond to conventional antipsychotic treatment, and clozapine is the first choice for treatment-resistant schizophrenia. Attenuated versions of the cognitive and emotional processing deficits in schizophrenia were reported to appear in the prodromal phase and in first-degree relatives of patients, consisting of a potential marker for the development of the disorder. We compared the performance of treatment-resistant and non-resistant schizophrenia patients and their first-degree relatives in cognitive tests and in a facial emotion recognition task. : Eight groups were enrolled for the study: 15 schizophrenia patients on clozapine (TRP) and 15 first-degree relatives of TRP; 15 non-resistant schizophrenia patients (NRP) and 15 first-degree relatives of NRP; and 60 healthy controls matched one by one to each of the participants in the previous groups according to age, gender, and education. Results: TRP were slower but as accurate as their matched healthy controls in the facial emotion recognition task, whereas NRP committed more emotional judgment errors and fared worse in the cognitive tests. Performance in the emotional task correlated with cognitive, PANSS, and BPRS scores. The relatives of schizophrenia patients performed similarly to healthy controls in the emotional task, although NRP first-degree relatives fared worse in the working memory test. Discussion: Both treatment-resistant and non-resistant schizophrenia patients have impaired facial emotion processing, but deficits are qualitatively different (time vs. judgment errors). Clozapine seems to enhance facial emotion recognition in TRP, although at the expense of time. The results are insufficient to support that first-degree relatives of schizophrenia patients have significant cognitive or emotional impairment.


Neuropsychological and personality assessments as a contribution for the differential diagnosis of factitious disorder and schizophrenia: a case report
Dulce R. Coppedê1, Graça M. Oliveira1, Maria Inês Falcão1, Jônia L. Felício1, Paulo C. Sallet2
1Serviço de Psicologia e Neuropsicologia, Instituto de Psiquiatria, Faculdade de Medicina da Universidade de São Paulo, São Paulo, SP, Brasil/2Instituto de Psiquiatria, Faculdade de Medicina da Universidade de São Paulo, São Paulo, SP, Brasil
Background: Although not rare, the diagnosis of factitious disorders is a challenge for the clinical practice. They include intentionally produced symptoms, whose purpose is to enable the subject to assume the sick role, without any external incentives for such condition, as regularly seen in malingering. When psychological signs and symptoms are predominant, the clinical picture may suggest the presence of a psychotic disorder. In these cases, the symptoms observed are inconsistent with the typical pattern of psychotic syndromes, the course and response to treatment are uncommon, and the symptoms are worsened when the patient knows he/she is being watched. V., male, 38 years old, was admitted to inpatient treatment after expressing suicidal ideation, with previous diagnosis of paranoid schizophrenia. He was in treatment with antipsychotic drugs in an outpatient basis. During hospitalization, the clinical picture observed was incongruent with the schizophrenia diagnosis. The patient's life history, the late onset of the condition, the quality of his interpersonal relationships, the apparent integrity of his personality and the visual hallucinations referred -" unusual in typical pictures -" triggered a diagnostic uncertainty. : Semi-directed psychological interviews were conducted. To evaluate several cognitive functions, the following tests were used: Wechsler Abbreviated Scale of Intelligence (WASI), Trail making Test, Stroop Color Word Test and Wisconsin Card Sorting Test. The personality was assessed with the Tematic Apperception Test (TAT) and the Desiderative Questionnaire. Results: The neuropsychological findings point to a general fluctuation of attentional processes, probably due to the anxiety generated by the task and the style of impulsive responses observed; good logical and temporal organization of speech and adequacy in relation to the patient's socio-cultural context; satisfactory semantic inventory; deficient logical matricial reasoning; and good performance concerning mental flexibility and ability to change cognitive strategies in response to changing environmental contingencies. The personality assessment, in agreement with clinical observations, points to the patient’s structural integrity. Formal changes of thought, disorganizations and defects of symbolization, characteristic of psychotic structure, were not observed. Rather, he was able to develop logical sequences and produce outcomes consistent with his narratives. However, fear, tension and suspense themes were apparent, as well as a recurring request for help. Faced with these contents, the defensive mechanisms mobilized generate a functioning marked by dramatic behavior, showed as high emotional expressiveness, indicative of a hysterical personality. The close relation between factitious symptoms and hysterical personality is reported by current research. Discussion: The personality and neuropsychological assessments have been of great value in the cautious exploration and implementation of differential diagnosis in psychiatry, enabling an appropriate direction for the treatment of patients.

Differential neuropsychological profile in asperger syndrome and schizophrenia
Louise Caruso1, Renato Del Sant2, Luciana de Carvalho Monteiro3
1Instituto de Psiquiatria do Hospital das Clínicas Faculdade de Medicina da Universidade de São Paulo, São Paulo, SP, Brasil/2Centro de Reabilitação e Hospital Dia do Instituto de Psiquiatria do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo, SP, Brasil/3Serviço de Psicologia e Neuropsicologia do Instituto de Psiquiatria do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo, SP, Brasil
Background: Schizophrenia and Asperger Syndrome (AS) may share some functional and cognitive changes, and the role of detailed neuropsychological assessments to inform differential diagnosis between these two conditions has not been fully established. Objective: To discuss evidence of differential cognitive features of schizophrenia and AS, based on: the case report of a patient with diagnostic uncertainty between the two conditions; and review of the literature on the profile of behavioral and cognitive features associated with schizophrenia and AS. : Detailed description of the clinical and comprehensive neuropsychological assessment of the patient (male, 37 years of age) using a standardized battery, aiming the mapping of his cognitive status. The data obtained were compared to the current published literature (indexed in Medline) over the past 10 years. Results: The clinical evaluation of the patient revealed signs and symptoms compatible with both the diagnoses of schizophrenia and AS. Results of the neuropsychological assessment of the patient showed good performance on tasks of verbal MEASURE when compared to executive functions, excellent working memory and attention, with lower scores in tests of visuospatial organization and planning, a high rate of perseveration, and failures of empathy. Discussion: The literature on the use of standard neuropsychological batteries in AS patients indicates performance deficits in the executive functioning, such as planning skills, in addition to a reduced empathic ability associated with a high performance on tasks testing verbal abilities, attention and working memory. Conversely, studies in schizophrenia subjects indicate presence of global cognitive impairment with an emphasis on verbal and visual memory, attention and executive functions. Thus the neuropsychological profile of the patient reported herein points to characteristics compatible with AS. Conclusion: This study highlights the importance of understanding the cognitive profile of patients in order to improve the differential diagnosis between psychiatric disorders that share similarities in symptomatic and functional impairment, such as schizophrenia and AS. 

Gender differences in neuropsychological performance in patients with first episode of psychosis

Jolanta Zanelli1, Abraham Reichenberg1, Kevin Morgan2, Paola Dazzan1, Craig Morgan1, Izabela Pilecka1, Paul Fearon1, Arsime Demjaha1, Carolina Zanelli1, Peter Jones3, Gill Doody4, Robin M. Murray1

1Institute of Psychiatry, London, United Kingdom/2University of Westminster, London, United Kingdom/3University of Cambridge, Cambridge, United Kingdo/4The University of Nottingham, Nottingham, United Kingdom

Background: This study examined the gender differences in neuropsychological performance in an epidemiological sample of first episode psychosis patients. The data were derived from a population based, case control study of first-episode psychosis. : The study identified all cases with a first episode of psychosis who presented to specialist mental health services in tightly defined catchment areas in South-east London, Nottingham and Bristol (UK) between September 1997 and August 2000. We compared neuropsychological tests performances of males and females who had a consensus ICD-10 diagnosis of schizophrenia (M = 45, F = 25), bipolar/mania (M = 14, F = 20), depressive psychosis (M = 15, F = 21), and from 148 controls (M = 67, F = 81). Results: In the schizophrenia group, both males and females were impaired on all neuropsychological domains. Gender differences were small and not statistically significant with females performed worse than males on language, attention and executive function domains and better than males on WAIS-R verbal intelligence and visual-spatial domains. Differences in neuropsychological performance between males and females with bipolar/manic disorder were restricted to language. By contrast in psychotic depressive disorder, females performed worse than males on all neuropsychological domains. Symptoms did not contribute to the observed gender differences. Discussion: There was strong evidence for disorder specific gender differences in neuropsychological performance. In our epidemiological study, gender related factors appear to mark the severity of cognitive deficits in depressive psychosis patients.

The Functioning Assessment Short Test (FAST) in patients with schizophrenia

Karine Zortéa1, Pedro Magalhães1,2, Adriane R. Rosa1, Lísia R. Guimarães1, Raffael Massuda1, David F. Lucena1, Júlio C. Walz1,2, Clarissa S. Gama1,2, Flávio Kapcizinski1,2, Paulo S. Belmonte-de-Abreu1,2
1Universidade Federal do Rio Grande do Sul, Hospital de Clínicas de Porto Alegre, Porto Alegre, RS, Brasil/2INCT, Porto Alegre, RS, Brasil
Background: Many studies have documented high rates of functional impairment among patients with SZ. However, the majority of the available instruments used to assess functioning have focused on global measures of functional recovery rather than specific domains of psychosocial functioning. Most of these instruments have important limitations for the use in psychiatry. The aim of the present study was to evaluate the psychometric properties of the Functioning Assessment Short Test (FAST) in patients with schizophrenia. :
Hundred and seven patients with schizophrenia and 108 controls were assessed in a University Hospital (Hospital de Clinicas de Porto Alegre, Brazil). FAST psychometric properties (internal consistency, concurrent validity, and test-retest reliability) were analyzed. Results: The internal consistency obtained was high with a Cronbach's alpha of 0.89. The FAST total score was higher in patients as compared with the control group (Z = 11.95, p < 0.001). FAST test-retest agreement was excellent (ICC = 0.93, 95%CI 0.81-0.97). Additionally, FAST displayed positive correlation with Brief Psychiatric Rating Scale (rho = 0.41, p < 0.001) and negative correlation with Global Assessment of Functioning Scale (rho = -0.71, p = 0.001). Discussion: Psychotic symptoms, comorbidity, functional and cognitive impairment contribute to decreased quality of life of patients with schizophrenia. It is important to obtain a valid and reliable instrument, capable of evaluating the functional domains in this pathology. In this context, FAST showed accurate psychometrics properties and was able to detect functional differences between patients with the diagnosis of schizophrenia and healthy subjects. 

Heterogeneity of executive functions in schizophrenia -
A systematic review

Arthur Berberian1,2, Alessandra G. Seabra1,3, Acioly T. Lacerda1,2, Rodrigo Bressan1,2
1Laboratório Interdisciplinar de Neuroimagem e Cognição (LiNC), Universidade Federal de São Paulo, São Paulo, SP, Brasil/2Programa de Esquizofrenia (PROESQ), Departamento de Psiquiatria, Universidade Federal de São Paulo, São Paulo, SP, Brasil/3Programa de Pós-Graduação de Distúrbios de Desenvolvimento, Universidade Mackenzie, São Paulo, SP, Brasil
Background: Impaired executive functioning (EF) has been reported in patients with schizophrenia, in individuals at clinical risk for schizophrenia, and in their first-degree relatives. Although there is a bulk of evidence suggesting the presence of fractions of EF in healthy individuals, two relevant issues regarding EF construct are still unclear when considering EF research in schizophrenia. The first one concerns EF organization and the second is related to the executive control of other cognitive processes. Several authors tend to agree with the unitary concept of executive process. However, another concept presumes that these processes are fractionated and may have different implications in behavior. The main aim of present study was to systematically review the literature on EF heterogeneity in schizophrenia to identify common dimensions that may be used as targets for cognitive interventions. : A literature search was performed using Medline with the following terms schizophrenia, schizoaffective, executive function, frontal lobe, frontal skills, executive skills, profile, frontal profile, executive profile, heterogeneity, specific deficit, component skills, cluster analysis, and factorial analysis. Only studies with original data evaluating the EF heterogeneity (at least one test for more than one dimension and/or ability) were included. Complex problem-solving tests without specifying scores for different EF dimensions were not included. Results: Of the 17,833 studies identified, 39 studies met all inclusion criteria. Six executive dimensions were identified: (1) Inhibition aspect, the capacity to deliberately inhibit automatic and dominant responses; (2) Working memory/updating capacity, which refers to the capacity to maintain temporal tags in mind, monitoring the items held with the purpose to replace them for newer ones when necessary; (3) Set shifting, which refers to the common cost taken to perform tasks that require disengagement from one process in order to undertake another; (4) Stimulus-driven responding, related to the incapacity to guide behavior by internal representation/intentions and, therefore, to primarily respond to external stimuli; (5) Output generation capacity. This ability refers to the high level of attentional control, which involves attentional allocation to regulate and maintain output of performance; (6) Abstraction. This dimension takes place when complex tasks are performed. Discussion: Although dissociated, poor performance in part of these factors (e.g. abstraction, output generation, and set shifting) may be obscured because it probably requires multiple cognitive processes rather than a single, unitary function. Furthermore, other idiosyncratic task requirements not related to target executive function might contribute to the formation of part of these factors, suggesting a strong sensibility to detect global EF impairment, but inappropriate specificity regarding the specific stage in which breakdown of EF processes takes place. This review demonstrates the scarcity and limitations of the methods used to investigate EF in schizophrenia and suggests a hybrid approach focusing on factor analysis mixed with the attempt to map aspects of the case study approach onto group analysis. Advantages of using this approach include the possibility to investigate EF organization among patients, relatives, and controls; to investigate relationships involving different EF and other features such as biological markers or functional outcome; to confirm previous theoretical models and testing the inclusion of new mechanisms in traditional models.

IQ measure in relation to the diagnosis and treatment of schizophrenia

Graça Maria R. Oliveira1, Monica Kayo2, Sandra M. K. Iso1, Helio Elkis2

1Serviço de Psicologia e Neuropsicologia, Instituto de Psiquiatria, Faculdade de Medicina da Universidade de São Paulo, São Paulo, SP, Brasil/2Programa de Esquizofrenia, Departamento e Instituto de Psiquiatria, Faculdade de Medicina da Universidade de São Paulo, São Paulo, SP, Brasil

Background: Cognitive deficit is a core feature of schizophrenia, influencing the clinical presentation and daily functioning of patients. It is usually related to negative and disorganized symptoms of the disease. Most studies in this field has analyzed specific aspects of cognitive functions, with only a few including IQ as a general measure of global functioning1. According to a metanalysis, subjects with schizophrenia are one or more standard deviations (SD) below the average of general population2, and the IQ deficit appears before the onset of psychotic symptoms. Some studies have shown that a lower premorbid IQ is likely to be a risk factor for psychotic episodes. However, IQ measurement is rarely used as marker or follow-up tool in patients with schizophrenia. In this study, we assessed the IQ of patients with recent onset schizophrenia, during acute exacerbation, within one week of the beginning of antipsychotic treatment and re-assessed after 12 weeks of treatment, after the remission of acute psychotic symptoms. : Twelve subjects with recent-onset schizophrenia (7 males, 5 females), with mean age of 26.08 (± 8.40) years, had their IQ assessed through the Wechsler Abbreviated Scale of Intelligence (WASI) at baseline and after 12 weeks. Mean time since diagnosis was 1.58 (± 2.54) years. Two subjects had a history of substance abuse (cannabis), but none were on active use. Five (41.7%) were initially treated with FGA and 7 (58.3%) were treated with SGA since the beginning. All patients were participating in a clinical trial aimed to assess time to response to antipsychotics. The steps of IPAP algorithm (www.ipap.org) was used to treat all the patients. Results: Baseline PANSS was 86.92 (± 14.64), decreasing to 50.36 (± 17.61) (p < 0.001) after 12 weeks of treatment with antipsychotics, while there was no difference between baseline measure of IQ (75.92 ± 14.88) and after 12 weeks (76 ± 12.79). There was no correlation between PANSS total score and IQ measure, neither with negative or positive subscales, according to Spearman correlations matrix, Bonferroni corrected. Among the 12 analyzed subjects, two were considered refractory after 12 weeks, and had a slightly decrease in IQ measure (from 84.50 ± 16.23 to 81.00 ± 21.21). However, due to the limited number of refractory it is not possible to make any conclusion from this IQ decrease. Discussion: The impairment intellectual of abilities are not just a consequence of the pathological process of disease onset. IQ measure remained stable during the trial, regardless of the PANSS scores. It is possible that refractory patients have a more severe cognitive impairment that can be detected at the beginning of treatment. IQ is one of the markers of increased risk of developing schizophrenia; however, this aspect must be further studied in a larger trial. References: 1. Leeson VC, Barnes TR, Hutton SB, Ron MA, Joyce EM. IQ as a predictor of functional outcome in schizophrenia: a longitudinal, four-year study of first-episode psychosis. Schizophr Res. 2009;107(1):55-60. 2. Heinrichs RW, Zakzanis KK. Neurocognitive deficit in schizophrenia: a quantitative review of the evidence. Neuropsychology.1998;12(3):426-45.

Digits span tests in siblings of patients with schizophrenia: a lack of association
Raffael Massuda1,2,3, Joana Bücker1,2, Natalia S. Kapczinski 1,2, Julio Walz1,2, Joana C. Narvaez1,2, Monise Costanzi2, Ramiro Reckziegel2, Ana C. Loredo1,2, Rafaela S. Silveira1,2, Maria I. R. Lobato1,3, Paulo S. Belmonte-de-Abreu1,3, Clarissa S. Gama1,2,3
1Programa de Pós-Graduação em Psiquiatria, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brasil/2INCT Medicina Translacional, Hospital de Clínicas de Porto Alegre, Porto Alegre, RS, Brasil/3Programa de Esquizofrenia, Hospital de Clínicas de Porto Alegre, Porto Alegre, RS, Brasil
Background: A wide range of neurocognitive deficits have been shown in schizophrenia (SZ). Recently, these impairments have been linked with BDNF gene-expression, suggesting neurocognitive deficits as potencial endophenotypes for SZ. Neurocognitive studies with first degree non-psychotic relatives of patients with SZ have show cognitive differences of this group compares to healthy controls, reinforcing the need of more studies to understand endophenotypes. In this study, we assessed cognition of SZ non-psychotic siblings with Digit Span of Wechsler Adult Intelligence Scale (WAIS) and compared with paired healthy controls. : Siblings (SB) of patients with SZ were recruited from the Schizophrenia Program at Hospital de Clinicas de Porto Alegre (HCPA). The patients were diagnosed with SZ by DSM-IV-TR. Thirty-three SB were selected to participate in the study. Exclusion criteria were presence of any psychiatric or substance dependence disorders in the last year and history of head trauma with extended loss of consciousness. Forty-three health controls were recruited from the community. A trained psychologist applied the WAIS Digit Span Test, which includes digits forward and digits backward. General linear model univariate analysis of covariance was performed. Digit span, digits forward and digits backward were the dependent variables. Age, sex and scholarity were covariates. Results: Response in Digit Span (p = 0,62), digits forward (p = 0,78) and digits backward (p = 0.98) were not different between siblings and healthy controls. Discussion: Our results have shown a similarity between SZ patients' siblings' subjects and healthy controls at Digit Span Test results. Studies with SZ patients' siblings using Digit Span Test have shown significant differences, but a small effect size, in larger samples than ours, once a small effect size would reflect a limited clinical effect. Our results and literature findings bring the questioning of the Digit Span Test feasibility to assess siblings. However, there is a need of further studies in siblings' cohorts to validate these results.

Schizoaffective disorders are closer to schizophrenia than bipolar disorder in rehospitalization rates: a 7-year outcome study

Rafael H. Candiago1,2, Karine Zortéa1,2, Lisia R. Guimaraes1,2, Raffael Massuda1,2, Paulo S. Paulo Silva Belmonte-de-Abreu1,2
1 Programa de Esquizofrenia, Hospital de Clínicas de Porto Alegre, Porto Alegre, RS, Brasil/2Programa de Pós-Graduação em Psiquiatria, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brasil
Background: The diagnostic cathegory of Schizoaffective Disorder (SAD), as a distinct entity between Schizophrenia (SZ) and major mood disorder, display low reliability and need substantial consideration. SAD (F25) and Schizophrenic Disorder (SD) (F20) share similar symptoms with subtle differences regarding balance among affective and psychotic symptoms and outcome. : To expand the issues of differences among SAD and SD we compared 7-year (2000-2007) rehospitalization rates (RHR) and length of stay (LOS) in the population of all patients (42,088 adults) in the State of Rio Grande do Sul (Southern Brazil) covered by the Public Heath System – SUS, with ICD-10 diagnosis of SD, SAD and Bipolar Disorder (BD). Results: BD subgroup displayed lower LOS (27,65 days) than SAD (39,63 days) and SD (43,8 days). RHR in 90, 180 and 365 days were also similar among SAD and SD, and higher than in BD, with similar pattern in survival curves. Discussion: The similar pattern of cumulative survival among SAD and SD differing from BD demonstrates that these two first disorders have similar outcomes regarding time to rehospitalization, and generates additional arguments for the need to the review the adequacy of keeping SAD as a different disorder or put it inside SD. This change will increase the access of SAD to adequate care, with relatively small increase in overall costs for the Medical Care System (with the inclusion of 10% of newly eligible patients to special treatments as high cost drugs and extended benefits such as bus passes, food tickets and financial support). Our results can contribute for this discussion of DSM-V and ICD-11, according the criteria used to examine the similarity between disorders and clusters. SZ and SAD show similar rehospitalization rates and these characteristics could be included into two validators items for a disorder: course of illness and treatment response. 

Acute and transient psychotic disorder in adolescents: clinical aspects and a 5 years follow-up
Roberto B. R. Taveira1, Daniela L. R. Taveira2, Leonardo F. Caixeta1, Marcelo Caixeta1, Paulo V. B. Azevêdo2, Thalita D. L. Quinan1
1Universidade Federal de Goiás, Goiânia, GO, Brasil/2Pontifícia Universidade Católica de Goiás, Goiânia, GO, Brasil
Background: The concept of ''acute and transient psychotic disorder '' has a complex provenance history in psychiatry. Previous authors had already noticed that some psychotic episodes came upon an acute way, differently from other entities, which had an insidious character. For them, some kind of degeneration was necessary to trigger its development. Latter, Kraepelin classified such disorder; he characterized it as "atypical" when compared to early dementia, maniac-depressive psychosis and schizophrenia due to many aspects later discussed. With Kraepelin definitions, other authors stablished with new categorizations, and now-a-days, some people consider those subdivisions as real entities, whereas others believe they are atypical presentations of others well-defined entities. : Twenty adolescents diagnosed with acute and transient psychotic disorder between January and June of 1998 were seen by three doctors separately. They were assessed upon seven visual analogue scales for: delusional-hallucinatory -polymorphism', physical aggressively, excitation, verbal output, environmental contact, orientation and foregoing stressors significance. Five years later, those patients were reassessed, and based on therapeutic data, laboratorial exams and new psychopathological-clinical elements, they were given different diagnoses. Results: All of the twenty patients firstly diagnosed as "acute and transient psychotic disorders' were classified in a new diagnostic category when reassessed during hospitalization, follow-up or five years after the first hospitalization. Ten patients fulfilled the criteria for "manic episode", four patients were included in the ''organic'' mental disorders category, two were diagnosed with paranoid personality, two with histrionic personality and two with schizophrenia. Discussion: This nosographic discussion is especially important concerning adolescents, since in this period of life there is a greater susceptibility to ''reactive'' psychosis, not to mention the more atypical presentations of entities such as the acute delirious mania. Also, they are a good subject of study as they usually are not under a pharmacological treatment, and we have the opportunity of a longer follow-up. Using phenomenology and visual analogue scales in these aspects: polymorphism, physical aggressively, excitation, verbal output, environmental contact, orientation, foregoing stressors significance, we could explain and expose different presentations in each entity, what helped us make the later diagnoses. According to our small sample, it seems to us that most of adolescents with acute psychotic presentations will evolve to a specific diagnose later, such as a bipolar disorder range, an organic pathogenesis or schizophrenia. Therefore, we are among the ones who think the -acute and transient psychotic disorders' are atypical presentations of others well-defined entities, and with an improved diagnosis technique we'll let such controversial diagnose behind.

Emotion recognition in subjects a ultra high risk for psychosis: a review
Paula A. Martins1, Priscila D. Gonçalves1, Luciana C. Monteiro1, Mario Louza1
1Instituto de Psiquiatria do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo, SP, Brasil
Background: Social cognition is the ability to perceive the intention and willingness of the other in a given context; it also includes skills in social perception, emotion recognition, attribution and empathy. It is considered a mediator between neurocognition and social functioning. Studies of cognition in subjects at ultra high risk (UHR) for psychosis has focused on deficiencies in cognitive functions like memory and attention. We reviewed studies about face emotional recognition in individuals at high risk for psychosis and hypothesizes that such difficulties may be potential markers of vulnerability for the development of psychosis. : We used national and international electronic databases; Medline, Lilacs and SciELO virtual libraries, from 2000 to 2011, and the following descriptors were used: "Emotion Recognition", "Early Psychosis" and "Ultra High Risk". Results: The search resulted in 29 articles, 11 for meeting the inclusion criteria, three others were selected for being cited in the articles mentioned and addressed the theme. The other 15 articles were excluded because they evaluated emotion recognition exclusively in patients with first episode and/or chronic schizophrenia and one because was a review. Those 14 studies compared different combinations of groups, UHR, first episode patients, schizophrenic patients, schizotypal patients, first and second degree relatives and control groups. Individuals at UHR for psychosis show impairment in several aspects of emotion recognition, especially in the ability to identify negative facial emotions. They also identify neutral expressions as negative. Discussion: These impairments in emotion recognition could be a predictor of conversion to psychosis, although it still has not been possible to exclude the influence of initial positive symptoms in the emotion recognition changes observed in this population. The studies presented some limitations concerning the criteria for UHR. Some of them follow the SIPS/SOPS criteria while others used genetic risk, schizophrenia relatives and schizotypy personality traits, according to the SPQ criteria. Other limitations presented concerning the use of various psychometric measures for the assessment of emotion recognition. 

Frequencies of comorbidity among children with early onset psychosis
Yuri Busin1, Tais S. Moriyama1, Ana C. Melcop1, Gabriela Siloto1, Felipe S. N. Machado1, Tatiane C. Ribeiro1
1Universidade Federal de São Paulo, São Paulo, SP, Brasil
Background: Child onset schizophrenia is a rare and severe mental disorder. It is considered a more severe presentation of schizophrenia that is commonly resistant to treatment, associate with neurological abnormalities and worse prognosis. There are few studies examining the frequencies of psychiatric comorbidity among psychotic child, most data points to alarming prevalence of up to 99% of comorbidity. Our aim is to estimate the frequency of other diagnosis in a sample of young child with early onset psychosis. : Eight children and adolescents with diagnosis of psychosis according to clinical psychiatric evaluation performed by a child psychiatrist were assessed for comorbidity using K-SADS PL. Age range varied from 6-17 and the majority of patients were girls 7(87,5%). A trained rater with experience in psychosis conducted all interviews. Results: All patients fulfilled criteria for schizophrenia according to K-SAD PL. Frequencies of comorbidity were overall high, most common diagnosis were ADHD 62,5%, oppositional defiant disorder 62,5%, social anxiety disorder 62,5%, depressive disorder 37,5%, agoraphobia and specific phobias 50%, generalized anxiety disorder 37,5% and enuresis 25%. Conduct disorder, tic disorders, anorexia and bipolar disorders were diagnosed in 12,5% of patients each. No diagnosis was made for encopresis, panic disorder, separation anxiety disorder, obsessive compulsive disorder, post-traumatic stress disorder, bulimia and substance misuse. Discussion: Overall frequencies of comorbidity are very high among children with early onset psychosis. This might reflect that early onset psychosis are core symptoms of a more widespread brain abnormality or that diagnostic criteria and assessment instruments for this population should be revised.

Duration of untreated psychosis in early onset psychosis

Felipe Salles Neves Machado1, Gabriela Rached El H. Siloto1, Yuri Busin1, Tatiane Cristina Ribeiro1, Ana Paula Melcop1, Taís S. Moriyama1, Rodrigo A. Bressan1
1Universidade Federal de São Paulo, São Paulo, SP, Brasil
Background: Early onset psychosis (EOS) is a rare condition defined herein as schizophrenia with onset before the 18th birthday. Duration of Untreated Psychosis (DUP) is an important determiner of prognosis for psychotic disorders. Scarce data exist on with factor are associate with early search for treatment in children with psychotic disorders. In one of the few available studies in the field. Schimmelmann et al. (2008) studied a population of adolescents and children with early onset psychosis and found that earlier age of disease onset, worse pre-morbid social adjustment and diagnosis of schizophrenia spectrum disorders was associated with longer duration of untreated psychosis (DUP). The reduction in DUP has been associated with a reduction in negative symptoms, suicidal behavior and improve de prognosis (Marshall, 2005). Additionally, patients with onset of psychotic symptoms before 18 years old has significantly longer DUP than patients with adult-onset psychosis (onset > age 18), suggesting that treatment delay may be a critical problem in this group. Treatment delay may be related to patient's clinical characteristics, accessibility and quality of mental health care, attribution models and coping capacities of social network, and patient’s willingness to see a psychiatrist (Schimmelmann, 2008). On the other hand, physicians and psychiatry themselves may be less aware of recognize EOP regarding the nature of psychiatry pathologies predating and overlapping EOP (Kim-Cohen, 2003; Rosen 2006). There are few studies on the assessment of variables associated to longer DUP in EOP. This is a preliminary analysis of an ongoing study that aims to identify DUP in EOP and its correlation with age of disease onset. : Eight patients with EOP were included in this study. Six (75%) patients fulfilled diagnostic criteria for schizophrenia, one (12,5%) for unspecified psychotic disorder, one (12,5%) for bipolar disorder with psychotic symptoms according to the DSM IV diagnostic criteria. Duration of untreated psychosis was determined according to best-provided information based on clinical interview with parents and child and contact with schoolteacher when appropriate. Child psychiatrists collected best time information about date when first psychotic symptoms were observed; psychotic symptoms were defined as presence of symptoms suggesting delusions or hallucinations or disorganized though, speech or behavior. Onset of adequate treatment was set as the moment when patients first receive an antipsychotic medication. Duration of untreated psychosis was calculating based on dates provided. Demographic and clinical variables were obtained from medical records. Mean duration of untreated psychosis was determined and DUP was correlated to age at disease onset. Results: DUP for this small sample of patients was 20.7 months (SD 26.3). No significant correlation was found for age at disease onset and DUP. Discussion: Duration of untreated psychosis in early onset schizophrenia is relative high. Effort should be made in understanding the factors associated with longer or shorter DUP in children that could help planning intervention to reduce length of untreated psychosis. Additionally, studies exploring specific pathways to care in adolescents and children with first episode psychotic are clearly warranted in order to develop specific strategies that could shorten treatment delays in these patients.

Is psychodynamic therapy an effective intervention for individuals at Ultra-high Risk (UHR) of psychosis? A case report

Paula Martins1, Silvia M. Arcuri1, Oswaldo Leite Netto1, Priscila D. Gonçalves1, Mario Louzã1

1Faculdade de Medicina da Universidade de São Paulo, ASAS, Departamento de Psiquiatria, São Paulo, SP, Brasil


Background: Little is known about the effectiveness of psychodynamic therapy (PD-T) in individuals at UHR to develop psychosis. We report a case that was followed for 12 months of PD-T with remission of prodromal symptoms. : Subject G., male, 21 years old, single was brought to our Early Psychosis Program (ASAS) by his parents, due to changes in behavior (he took a train "without certain destination" and "disappeared" for some hours, without calling his parents), difficulties in his studies (he lost college exams), social withdrawal and suspiciousness. He was evaluated with the Structured Interview for Prodromal Symptoms (SIPS) total score was 37 and the Global Assessment of Functioning (GAF) 71. He fulfilled criteria for UHR (attenuated positive symptoms and schizotypal personality disorder + functional deterioration). Baseline neuropsychological assessment showed cognitive performance within average, with mild difficulties in long term visual memory. He underwent weekly sessions of PD-T, and was clinically evaluated every three months. No medication was prescribed during the 12-month follow up. Results: From a psychodynamic point of view, considering the psychoanalytical theoretical background of Melanie Klein, initial symptoms included, intolerance to frustration, difficulties in integrating good (gratifying, loved) and bad (frustrating, hated, persecutory, aggressive) aspects of the object (splitting), idealization and low self esteem. Excessive attachment and dependence to parental figures (partial object relations) were also observed. During PD-T he demonstrated good insight, and the process of reflecting upon his feelings and thoughts, discussing them with his psychotherapist (SMA), probably enabled him to integrate good and bad aspects of his personality. Such insights may have helped him to overcome ambivalence, increasing his tolerance to conflict and frustration. The clinical evaluation after 6 months showed that he was able to return to College, began to work as a trainee and was soon promoted, successfully completing half term exams (Scale of Prodromal Symptoms - SOPS = 21 GAF = 76). He also engaged in peer social and affective relations. After 12 months of follow-up his SOPS was 12 and GAF was 83 and he maintained similar results in his neuropsychological tests. Discussion: From a PD-T perspective the remission of prodromal symptoms might be associated to the development of mature aspects of his personality, what could be seen as a more flexibility in shifting from a schizo-paranoid to a depressive position (Melanie Klein). In the beginning of the PD-T process he was experiencing paranoid anxiety, splitting of objects (all "good" or all "bad"). Along the PD-T the development feelings of guilt, grief, and the desire for reparation might have contributed to a more integrative perception (whole-object) of himself and others. Considering the limitations of a single case report, we suggest that PD-T may be a useful tool to help UHR subjects to overcome symptoms that may act as triggers of a full-blown psychosis. A better understanding of the specificity and efficacy of PD-T as a choice of treatment for UHR individuals is needed.

Prodromal questionnaire: translation, adaptation to Portuguese and preliminary results in high risk individuals and first episode psychosis

Priscila D. Gonçalves1, Paula Martins1, Pedro Gordon1, Mario Louzã1

1Departamento de Psiquiatria, ASAS, Faculdade de Medicina da Universidade de São Paulo, São Paulo, SP, Brasil


Background: The identification of subjects at ultra high risk to develop psychosis is usually done specialized centers, by complex instruments, such as the Structured Interview for Prodromal Symptoms (SIPS) or the Comprehensive Assessment of At Risk Mental States (CAARMS). Simple screening self-rating scales are necessary for a widespread evaluation of UHR subjects in other contexts such as primary care units or schools. The Prodromal Questionnaire (PQ) is a 92-item self-report screening tool for individuals at UHR to develop psychosis. It has four major subscales: positive, negative, disorganized and general symptoms and has good validity when compared to the golden standard instrument (SIPS) (Loewy et al., 2005). We present its translation to Portuguese and preliminary results in URH and first episode psychosis. : The PQ was translated from English to Portuguese by two bilingual researchers from the research program on early psychosis of the Instituto de Psiquiatria HCFMUSP (ASAS – “Evaluation and Follow up of Adolescents and Young Adults in São Paulo”). The study participants were individuals who met the phone screening criteria (check list of symptoms for at least two weeks: changes from the usual behavior, social withdrawal, odd thoughts, strange or unreal sensations, preoccupation with particular ideas or thoughts, unusual experiences such as seeing or hearing things that are not there, isolation, poor performance at school or work) and came to a personal interview, when a thorough evaluation including: the Brazilian version of the Prodromal Questionnarie (BPQ), SIPS and neuropsychological assessment was performed. Results: Seven URH individuals (5 male and 2 female), aged 16-26 (mean: 20.3 ± 3.4 years) who contacted ASAS fulfilled the BPQ. Their BPQ positive symptoms scale mean was 13.0 ± 10.0 points, negative symptoms scale was 10.1 ± 4.6 points, disorganized symptoms scale was 5.3 ± 3.2 points and general symptoms scale was 7.6 ± 1.9 points. Four first episode patients (3 male and 1 female), aged 13-20 (mean: 17.0 ± 2.94 years) who contacted ASAS also fulfilled the BPQ. Their BPQ positive symptoms scale mean was 33.0 ± 10.0 points, negative symptoms scale was 12.5 ± 3.78 points, disorganized symptoms scale was 8.5 ± 1.3 points and general symptoms scale was 10.25 ± 1.9 points. Discussion: Considering the mean value of the BPQ positive symptoms subscale of our UHR sample, our results are in line with Loewy et al. (2005). They consider that a cutoff point of the positive scale of 14.0 points (71% sensitivity and 81% specificity) indicates that the subject is at UHR for psychosis. Chiu et al. (2010) translated the PQ to Chinese and compared the results of 3 groups: UHR, psychosis and healthy subjects. Their results for the PQ positive scale were: 12.9 points ± 7.0, 21.9 points ± 7.0 and 5.4 points ± 5.1 respectively. Their findings are similar to ours, suggesting that the BPQ is able to detect UHR subjects and can also measure patients already with an established psychosis. Even thought our samples are very small, our results indicate that the BPQ is useful instrument for screening subjects at UHR, before they are thoroughly evaluated.

Cognitive and neurological deficits in children and adolescents with early onset psychosis
Gabriela Rached El H. Siloto1, Felipe Salles Neves Machado1, Yuri Busin1, Tatiane Cristina Ribeiro1, Ana Paula Melcop1, Taís S. Moriyama1, Rodrigo A. Bressan1
1Universidade Federal de São Paulo, São Paulo, SP, Brasil
Background: There is growing awareness that cognitive deficits in schizophrenia are a core feature of the disorder and cannot simply be dismissed as secondary consequences of psychotic symptoms. The degree of cognitive impairment is greater in child- and adolescent-onset than in adult-onset patients. Furthermore schizophrenia is considered to be a disorder with neurodevelopmental roots reflected in findings of neurological abnormalities and neurophysiological impairments. The aim of this study is to estimate the frequency of neurodevelopmental abnormalities in a sample of children and adolescents diagnosed with early onset psychotic disorder. : A total of 13 patients were included in this analysis, 11 had been diagnosed by a child psychiatrist as schizophrenic according to DSM IV criteria, 2 as psychotic disorder not other specified (ongoing investigation), 8 of than also been interviewed by an independent trained psychologist using KSAD-PL and all fulfilled diagnostic criteria for schizophrenia. Data collection was based on clinical interviews with patients and their parents, review of medical records and clinical examination. Results: 46,13% presented history of poor social performance, 7,69% seizures and 53,8% had previous history of learning difficult. Discussion: Most of the children and adolescents from our sample had a history of neurodevelopmental abnormalities preceding psychotic symptoms onset. This is in line with previous studies. Early onset psychosis seems to be a manifestation of a broader phenotype, characterized by multiple neurodevelopmental deficits. Those deficits might engender special needs that should be considered for adequate treatment and prognosis of such patients.

Evidence of psychomotor dysfunctioning in children with bipolar disorder and psychotic symptoms: report of two cases


Margareth Dreyer1, Sheila Caetano1, Lee Fu I 1, Cristiana Rocca1

1Departamento e Instituto de Psiquiatria, Faculdade de Medicina da Universidade de São Paulo, São Paulo, SP, Brasil

Background: Studies of patients with bipolar disorder show the presence of cognitive deficits, which are more pronounced in patients with psychotic symptoms. However, there are no studies about the presence of psychomotor deficits in these individuals. We examined the psychomotor profile of two patients with bipolar disorder and psychotic symptoms accompanied at Hospital Dia Infantil do Instituto de Psiquiatria: G. (10 years and 9 months) and L. (13 years and 10 months). They are polimedicated. : Patients were evaluated for static and dynamic balance, body scheme, handedness and lateral preferences, spatial-temporal organization, gross and fine motor skills. We used the following instruments: Psychomotor Battery (V. Da Fonseca), The Draw a Person Test (F. Goodenough), Psychomotor Examination (G. Rossel), Rhythmic Structures Test (M. Stambak) and The Rey Complex Figure. Results: We found deficits in both patients on the following areas: Tonicity: hypertonicity in superior limbs, expressed by poor extensibility of arms; 2) Balance: difficulties in dynamic balance tasks; 3) Body scheme representation: low scores compared to expected to chronological age 4) Handedness: Both boys are right handed (preferred ear, foot and eye also defined to the right) but there's no systematization of left and right concepts in others); 5) Spatial-temporal Organization: difficulties of reproduction of rhythmic structures, poor visuo-spatial perception, planning and calculation, both results show percentile below 10 points. 6) Gross motor skills (difficulties in dissociating inferior and superior limbs in action), difficulties in activities that include global dynamics 7) Fine Motor skills (handwriting difficulties, handgrip on pencils, association of fingers). Discussion: All the achievements in motor function coordinates found an intention -" the object of study Psychomotricity -" reveal difficulties in the praxis spheres. In both cases we found delays in Psychomotor development such as: tone and posture -" balance (1st neurofunctional Unit Luria). These are reflected on all subsequent acquisitions and more complex dynamics, such as praxis and fine motor skills (3rd Neurofunctional Unit Luria). The significantly lower results in tests of the Human Figure (mental age = 5 years and 6 months for G. and 6 years for L.) appear to reflect the difficulties of psychodynamic ego function in the scheme and body image. Psychomotor disfunctioning coexist with psychotic symptoms in patients with bipolar disorder. We can assume that despite the diversity of its manifestation, this aspect also part of the framework of childhood psychoses, and underscores the importance of psychomotor approach as part of a team approach. Intentional motor activities, organized to achieve a goal are the object of study of Psychomotricity. In both cases we found delays in Psychomotor development such as: tone and posture -" balance (1st neurofunctional Unit Luria). These are reflected on all subsequent acquisitions and more complex dynamics, such as praxis and fine motor skills (3rd Neurofunctional Unit Luria). The significantly lower results in tests of the Human Figure (mental age = 5 years and 6 months for G. and 6 years for L.) appear to reflect the difficulties of psychodynamic ego function in the scheme and body image. Psychomotor disfunctioning coexist with psychotic symptoms in patients with bipolar disorder. We can assume that despite the diversity of its manifestation, this aspect also part of the framework of childhood psychoses, and underscores the importance of psychomotor approach as part of a team approach.

Increased learning and social impairment in children at risk for psychiatric disorders in a Brazilian community sample

Pedro M. Pan1, Thomas P. Bernardes1, Livia Valim1, Carlos F. Silva 1, Roberto G. Macedo1, Luiza Halang1, Ary Gadelha1, Tais
Moriyama1, Giova nni A. Salum2, Rodrigo A. Bressan1


1Programa de Esquizofrenia (PROESQ), Universidade Federal de São Paulo, São Paulo, SP, Brasil/2Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brasil

Background: Child psychiatric disorders are associated to poor outcomes in social and educational development. Early identification
of individuals at risk for these disorders may reduce morbidity and avoid chronicity. In this study, we evaluate the relationship between the risk for childhood psychopathology and three development outcomes - social behaviour, learning problems, and burden to others. : We evaluated 6 to 12 years old children from the “Scholar High Risk Study for the Development of Childhood Psychopathology and Resilience – the Prevention Study”. Biological parents of 2554 children from public schools in São Paulo were evaluated using the Strengths and Difficulties Questionnaire (SDQ). We used total symptom score o group children in three groups: normal (Nor), borderline and abnormal (Abn), as suggested by the author of the instrument. We considered the borderline group as the “at risk” group (AtR).
The SDQ also evaluates how the children’s difficulties cause burden to others, problems in friendships and classroom learning. Results: The mean age of the sample was 8,61 years (SD:1,71). The likelihood of children in the AtR group having their difficulties considered a burden to the family was statistically significant, in a “dose-dependent” fashion when compared to the Normal group (AtR vs Nor - OR 3,94; 95%CI 2,80-5,57; p < 0,0001/Abn vs. Nor - OR 9,68; 95%CI 7,15-13,10; p < 0,0001). The same pattern was found in friendship (AtR vs. Nor - OR 4,31; 95%CI 2,87-6,48; p < 0,0001/Abn vs. Nor - OR 11,70; 95%CI 8,30-16,50; p < 0,0001) and learning variables (AtR vs. Nor - OR 4,79; 95%CI 3,54-6,31; p < 0,0001/Abn vs. Nor - OR 11,93; 95%CI 9,05-15,79; p < 0,0001). Discussion: We found an increased probability of poorer development outcomes (friendship and learning problems, burden to others) in the “at risk” group for childhood psychopathology when compared to the “normal” group. Thus, children at risk for mental disorders should be adequately followed because they already show difficulties in learning and social skills, and represent a burden to their family.

Behavior problems in children of parents with psychosis

Elisa K. Gutt1, Sandra Petresco1, Renata Krelling1, Francisco Lotufo-Neto1, Ricardo A. Moreno1, Geraldo F. Busatto1


1Universidade de São Paulo, São Paulo, SP, Brasil

Background: Several studies have been conducted with high-risk children for psychosis to observe developmental abnormalities that indicate vulnerability to psychosis and other psychiatric disorders in adulthood. These abnormalities include: delays in attainment of speech and motor milestones; poor social competence; deficits in attention; and presence of positive formal thought disorder, affective disorders, anxiety disorders, irritability and hostility behaviors. Studies with these children can contribute to understand vulnerability signs for psychotic and others mental disorders in adulthood, as well as provide hints on how to prevent mental disorders in at-risk populations. This study compared children at risk for psychosis with control children with the specific purpose of investigating differences in behavior problems as assessed with a standardized instrument, the Child Behavior Checklist (CBCL). : A comparative study was conducted including two samples of children aged 6 to 18 years: (1) one child randomly selected per family from all female outpatients with schizophrenia or bipolar disorder referred to an university psychiatric institute in São Paulo city, Brazil; (2) one child per family from a random sample of female outpatients referred to the gynecologic clinic of the same university. In both groups, SCID (Structured Clinical Interview for DSM-IV) was applied to mothers to identify psychiatric disorders, and the CBCL (Achenbach and Rescorla, 2001) was used to assess child behavior problems. The CBCL was applied by an interviewer because of the low educational level of subjects. Each instrument was applied by a different interviewer; all of them extensively trained psychologists or psychiatrists. Mothers and adolescents were interviewed by professionals blind to SCID results and diagnostic status of mothers. Data analysis was performed with the Statistical Program for Social Sciences (SPSS). Mean scores for CBCL broad-band and narrow-band scales were compared using Mann-Whitney test. Pearson’s chi square was used for categorical data. Results: There were no differences between groups in child gender (42.9% male x 57.1% female in control group, 41.2% male x 58.8% female in psychosis group; p = 0.88), and mean age of children (12.3 years in control and 12.17 years in psychosis group; p = 0.15). When examining between-group differences in mean raw-scores obtained in CBCL broad-band and narrow-band scales, significant distinctions were noted in the following scales: anxiety/depression problems (psychosis group = 7.61; control group = 6.20; p = 0.04); somatic problems (psychosis group = 3.39; control group = 2.27; p = 0.02); rule breaking problems (psychosis group = 2.97; control group = 2.85; p = 0.04); internalizing problems (psychosis group = 16.04; control group = 12.61; p = 0.01); and total problems (psychosis group = 49.51; control group = 40.03; p = 0.02). Discussion: Significantly higher indices of anxiety/depression problems, somatic problems, internalizing problems and rule breaking problems were detected in children at risk for psychosis relative to control children, in accordance with previous literature findings. Interventions for children at risk for psychosis should focus at these behavioral problems and their impact on their lives.

The evaluation of predictors of psychosis and bipolar disorder development in individuals presenting at-risk mental states – the PRISMA clinic protocol

Paula F. R. Silva1, Ary Gadelha1, Pedro M. Pan Neto1, Taís S. Moriyama1, Ana Soledade Graeff-Martins1, Elisa Brietzke1, Rodrigo A. Bressan1


1Universidade Federal de São Paulo, São Paulo, SP, Brasil

Background: The study of the phases that precede the onset of severe psychiatric disorders, such as schizophrenia and bipolar disorder has been proving to be a new and promising path to reduce the impact of these conditions, considering that recognition and early intervention could help delay or even prevent their onset or reduce their severity. Recent evidence suggests that it is possible to identify individuals presenting at-risk mental states (ARMS) based on their clinical evolution. Efficient mechanisms to predict which individuals will develop these disorders are still needed, while well established ways of approach and treatment should be discussed. The PRISMA clinic is a multiprofessional government funded outpatient facility of the Psychiatry Department of the Federal University of São Paulo (Unifesp) in São Paulo, Brazil. It was created to identify and offer treatment to individuals presenting at-risk mental states. The objective of this study is to describe the PRISMA clinic experience in evaluating the predictors of psychosis and bipolar disorder in individuals presenting at-risk mental states. : In the PRISMA clinic, a prospective study will follow 200 individuals aged 12 to 25 years, of which 100 ARMS and 100 healthy controls, during a one year period. Baseline and first year measures will be compared in order to investigate the roles of different variables in the prediction of conversion to bipolar disorder or psychosis. All individuals will go through a baseline evaluation that will include a psychiatric consultation and the use of diagnostic instruments (Comprehensive Assessment of At Risk Mental State, Young Mania Rating Scale Beck Depression Inventory). Once the inclusion criteria are met, posterior evaluation (K-SADS or SCID, neuropsychological evaluation, neuroimaging, genetics, bio marker measurements) and trimestral reassessments (CAARMS, YMRS) will take place. At the end of the one year period, the other exams will be repeated. Primary outcome measures will be (1) onset of manic or hypomanic episode during follow-up or initiation of use of mood stabilizers as recommended by the attending psychiatrist, or (2) onset of onset of psychotic episode during follow-up or initiation of use of antipsychotics as recommended by the attending psychiatrist. Secondary outcome will be worsening of the prodromic symptoms as indicated by the CAARMS scores. Results: This is an on-going study. So far, we have no preliminary results. Discussion: This study brings to Brazil a promising research line already consolidated in other countries, on the phenomenologic aspects of pre-morbid states of severe psychiatric disorders.

Nutritional evaluation of individuals at ultra high risk for psychosis

Cristina S. A. Correa1, Lizandra R. Silva1, Rodrigo B. Mansur1, Ary Gadelha1,2, Pedro Pan Neto1,2, Paula F. R. Silva1, Rodrigo A. Bressan1,2, Elisa Brietzke1

1Programa de Reconhecimento e Intervenção em Indivíduos em Estados Mentais de Risco, Universidade Federal de São Paulo, São Paulo, SP, Brasil/2Programa de Esquizofrenia, Universidade Federal de São Paulo, São Paulo, SP, Brasil

Background: Environmental factors have been suggested as relevant factors in pathophysiology of psychosis. Among those, the diet content of specific nutrients could potentially be implicated, although they have been insufficiently studied. Polyunsaturated omega 3 fatty acids supplementation has been postulated as beneficial in some psychiatric conditions such as schizophrenia, depression, aggressive behavior and ADHD. Since there are no studies evaluating diet content of Omega 3 fatty acids, we elaborated a protocol of nutritional evaluation in individuals at risk for psychosis, emphasizing determination of Omega 3 diet content. : One hundred individuals classified as Ultra High Risk for Psychosis will be compared will the same number of age and gender matched healthy controls. All of them will be submitted to a detailed anthropometric evaluation. In addition we will investigate the content of micronutrients in diet, specifically Omega 3 and Omega 6 content. Nutritional status will be evaluated using anthropometric parameters such as weight, height, BMI, circumferences and cutaneous folds, according with the standardized and age adjusted measurements. The diet content of nutrients, including Omega 3 will be assessed trough two food diaries one recordatory record and one instrument with the frequency of ingestion of different types of food. Data regarding the content of nutrients will be extracted using the software Darwin professional. Data will be tabulated and analyzed using SPSS 17.0. Results: Results will be presented in the poster. Discussion: This is the first study evaluating diet content of Omega 3. If the findings confirm the presence of a low diet content of this nutrient in individuals at risk for psychosis, a possible eficacy of Omega 3 supplementation in prevention of psychosis will be reinforced.


From at risk mental state to affective psychosis: a case report 

Elson Asevedo1, Graccielle R. Cunha1, Ary Gadelha1,2, Paula F. R. Silva1, Pedro Pan Neto1, Rodrigo B. Mansur1, André Zugman1, Elisa Brietzke1, Rodrigo A. Bressan1,2

1Programa de Reconhecimento e Intervenção em Indivíduos em Estados Mentais de Risco, Universidade Federal de São Paulo, São Paulo, SP, Brasil/2Programa de Esquizofrenia, Universidade Federal de São Paulo, São Paulo, SP, Brasil

Background: Bipolar Disorder (BD) has been recognized as a progressive illness, with the first manic/hipomanic episode being preceded by subclinical symptoms of variable duration (prodrome). During this phase, the condition challenges the current nosology offering a considerable diagnostic difficulty. The symptoms used to be interpreted as associated with other conditions such as major depressive disorder, ADHD or substance abuse. The objective of this description is to report the evolution of prodromal symptoms until the eclosion of a manic episode. : The clinical case of a young man with prodromal stages of BD was followed up in an early psychosis program and is reported. Results: A 10-year old boy with positive history for BD reported onset of depressed mood with frequent crying, irritability, a persistent thought of running away from home, reduction in pleasure in everyday activities, apathy, difficulty of concentration and refuse to stay in school. The patient received risperidone 0,5 mg without response. Six weeks after, the medication was changed for sertraline 25 mg. After one week the patient presented talkativeness, psicomotor agitation and jocosity for three weeks. The medication was switched to imipramine 25 mg and patient became socialy isolated with severe depressive mood and refusing food. The medication was changed to metilphenidate 10 mg for two years with partial remission of the symptoms. Three years later, patient was referred to a specialized service in childhood psychiatry where he received a diagnosis of ADHD predominantly inattentive and "bipolar spectrum". The prescribed treatment was valproate 500 mg plus metilphenidate 10 mg with remission for two years. During this time, he was submitted to a neurocognitive evaluation, which showed a borderline IQ. At the age of 14, patient experienced symptoms such as an excessive preocupation with bacteria and contamination, an intense and persistent ''fear of ilicit drugs'', visual hallucinations of smoke near other people and the feelling of being observed. Prodromal psychosis was considered a valid diagnosis and olanzapine 5 mg was started. Since the parents refuse keep the patient in treatment, olanzapine was interrupted. After four months patient present mild restlessness and talkativeness. After two weeks a full blond manic episode ecloded with psychomotor agitation, discourse with sexual content, marked reduction in the need of sleep and considerable impairment in functioning in home and school. A diagnostic of manic episode was done and lithium 600 mg and olanzapine 5 mg with good response. After remission, the neurocognitive evaluation was repeated resulting in mild mental retardation. Discussion: This clinical case ilustrates the evolution of prodromal stages of BD, including the diagnosis implications. Since the prodrome can be recognized, its approach could potentially offer a good possibility of prevention of deleterious consequences of the clinical and neurobiological progression. 

Stress, HPA function, and risk for psychosis

Elaine Walker1, Jean Addington2, Kristin Cadenhead3, Ty Cannon4, Barbara Cornblatt5, Robert Heinssen6, Tom McGlashan7, Dianna Perkins8, Larry Seidman9, Ming Tsuang10, Scott Woods11, Hanan Trotman1

1Emory University, Atlanta, GA, United States/2University of Calgary, Calgary, AL, Canada/3University of California, San Diego, CA, United States/4University of California, Los Angeles, CA, United States/5Long Island − Jewish Hospital, Long Island, NY, United States/6NIMH, Bethesda, MD, United States/7Yale University, New Haven, CT, United States/8University of North Carolina, Chapel Hill, NC, United States/9Harvard University, Boston, MA, United States/10University of California, San Diego, CA, United States/11Yale University, New Haven, CT, United States


Background: There has been increasing interest in the prodromal period prior to the onset of psychotic disorders, with the assumption that multiple factors converge at this point and give rise to the onset of psychotic symptoms. The hypothalamic-pituitary-adrenal (HPA) axis is among the brain systems of interest because it; a) mediates one component of the biological response to stress, and b) appears to undergo normative maturational change in conjunction with pubertal development, leading to heightened sensitivity to stress. In this presentation, we examine self-reported stressful events and cortisol secretion in healthy subjects and individuals at clinical risk for psychosis. It was hypothesized that levels of self-reported stress will be positively correlated with current salivary cortisol, and that the relation will be more pronounced for youth at clinical risk. Based on the hypothesis that adolescence/young adulthood is linked with increasing stress sensitivity, relations of age with self-reported stress and cortisol were also tested. : Participants are 110 healthy controls and 160 individuals who meet criteria for the prodrome to psychosis based on the Structured Interview for Prodromal Syndromes. Mean age is 19 (SD = 4.4, range 13 to 30) years. A self-report measure of daily stress (Daily Stress Inventory) and multiple measures of salivary cortisol were obtained during baseline assessment. Results: Regression analyses, controlling for psychotropic medication, revealed a significant relationship between self-reported stress and cortisol secretion for both diagnostic groups. There was a trend toward an age-related linear increase in self-reported daily stress for both groups, but a highly significant main effect of diagnostic group, with prodromal subjects reporting more stressors than controls. Analyses of nonlinear components of developmental changes in stress indicated a quadratic function with increases in adolescence and a decline in early adulthood. Analysis of cortisol revealed an interactive effect of Age X Diagnostic group, with, as predicted, a more pronounced age-related linear increase for prodromal youth compared to healthy controls. Discussion: The present study revealed a positive association between self-reported stress and cortisol secretion for both diagnostic groups. The findings are consistent with previous reports of maturational increases in stress and cortisol secretion during the course of normal adolescence, with a more pronounced increase in at-risk youth. The findings will be discussed in the context of rapidly accumulating evidence of neuromaturational changes in stress sensitivity, the triggers of this process, and its' role in psychosis.

Decreased in thioredoxin reductase activity in patients with schizophrenia

Eduardo S. Bohme1,2, Raffael Massuda1,2,3, Laura Stertz1,3, Gabriel R. Fries1,3, Mauricio Kunz1,3, Maria I. R. Lobato1,2, Clarissa S. Gama1,2,3, Paulo S. Belmonte-de-Abreu1,2

1Programa de Pós-Graduação em Psiquiatria, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brasil/2Programa de Esquizofrenia, Hospital de Clínicas de Porto Alegre, Porto Alegre, RS, Brasil/3INCT Translational Medicine, Hospital de Clínicas de Porto Alegre, Porto Alegre, RS, Brasil


Background: Oxidative stress (OS) is defined as an imbalance between reactive oxygen species and antioxidant response. There is strong evidence that OS may play an important role in the pathophysiology of schizophrenia (SZ). Our group has shown previously impairment in antioxidant defenses in patients with SZ. High serum levels of superoxide dismutase (SOD) and increased lipid peroxidation, measured by the thiobarbituric acid reactive substances (TBARS) have been seen in patients with SZ. Thioredoxin reductase (TrxR) is an enzyme that composes the thioredoxin system (TS). It has a large number of functions as DNA synthesis, defense against apoptosis and defense against oxidative stress. Dysfunctions in TS have been shown in a large number of diseases, but there are no studies measuring the TrxR activity in patients with SZ. : Thirty-three patients with SZ were recruited from the Schizophrenia Program at Hospital de Clinicas de Porto Alegre (HCPA). The patients were diagnosed by DSM-IV-TR. Twenty-nine controls were recruited from the community. Each subject had 5 ml blood samples collected by venipuncture. Serum thioredoxin reductase levels activity were by continuous spectrophotometric. Results: Patients with SZ have significantly lower TrxR activity compared to healthy controls (p < 0.01). Discussion: As far as we aware this is the first report measuring the TrxR activity in patients with SZ. The present findings provide additional evidence of increased oxidative stress in schizophrenia. Other studies have demonstrated impairments in TS in patients with SZ. Oxidative markers and their relation to neurotrophins and inflammatory markers would be used as biomarkers in clinical setting. However, there is a need of population studies for a biomarker validation in SZ.

Comparison of brain-derived neurotrophic factor serum levels in psychotic and in remission patients with schizophrenia, psychotic manic and euthymic patients with bipolar disorder and healthy subjects

Leonardo A. Sodré1,2, Bruna S. Panizzutti3, Vauto A. Mendes2,3,4, Felipe B. P. Costa3, Daniel R. Farias3, Camila R. Selbach3, Bruno P. Mosqueiro3, Roberto K. Jaconi5, Alexandra I. Zugno6, Raffael Massuda1,2,4, Clarissa S. Gama1,2,3,4

1INCT Translational Medicine, Hospital de Clínicas de Porto Alegre, Porto Alegre, RS, Brasil/2Programa de Pós-Graduação em Psiquiatria, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brasil/3Departamento de Psiquiatria, Hospital de Clínicas de Porto Alegre, Porto Alegre, RS, Brasil/4Programa de Esquizofrenia, Hospital de Clínicas de Porto Alegre, Porto Alegre, RS, Brasil/5Programa de Residência em Psiquiatria, Hospital São Pedro, Porto Alegre, RS, Brasil/6Programa de Pós-Graduação, Universidade do Extremo Sul Catarinense, Criciúma, SC, Brasil


Background: The acute psychotic syndrome in patients with schizophrenia (SZ) and manic patients with bipolar disorder (BD) is still a clinical diagnosis challenge. Despite their similarities, the literature suggests that these disorders involve different pathophysiological mechanisms. The aim of this study is to compare the serum levels of Brain-Derived Neurotrophic Factor (BDNF) between these two disorders in psychotic episodes and in remission. : We selected, by DSM-IV structured clinical interview, eight patients with BD in psychotic manic episode, nine patients with SZ in acute psychosis, ten euthymic BD patients, ten SZ patients in remission and eleven healthy subjects. Patients with chronic non-psychiatric clinical comorbidity, substance abuse in the last week and pregnant women were excluded. The severity of the psychotic episode was measured with the Brief Psychiatric Rating Scale (BPRS). BDNF serum levels were examined by sandwich ELISA. Results: There was no statistical difference between groups regarding age (p = 0.574) and illness duration (p = 0.428). Four acute psychotic patients with SZ (44%) and three psychotic manic patients (37.5%) were using medication regularly. Of them, two acute psychotic patients with SZ (22.2%) and one manic BD patient (12.5%) were in regular use of clozapine. All non-psychotic patients were in regular pharmacological treatment, whereas all of the stable patients with SZ were on clozapine. No significant difference was found in BDNF serum levels between all the groups. However, an increased tendency in BDNF serum levels in acute psychotic episode patients with SZ were found (p = 0.081). Discussion: We believe the results were affected by the small number of subjects in each group. An increased tendency in BDNF serum levels in acute psychotic patients with SZ was found. Although the clinical presentations of psychotic episodes may be similar between SZ and BD, these results corroborate findings in the literature that both diseases have distinct biochemical profiles, underpinning their pathophysiological mechanism. The difference in drug treatment would be a result bias. However, 100% of patients with SZ in remission were under clozapine, a medication that present properties of BDNF increasing levels. However, it is still necessary to enlarge the sample for statistical evidence of the observed results. Future studies with a larger sample should be conducted to confirm our results.

A first episode of psychosis in a sickle cell disease patient: the role of psychosocial stressors in psychosis

Bruno P. F. Souza1, Renata Krelling1, Martinus Th. van de Bilt1


1Instituto de Psiquiatria da Faculdade de Medicina da Universidade de São Paulo, São Paulo, SP, Brasil

Background: The relationship between sickle cell disease and mental illness is controversial in literature. Even mental illnesses with high prevalence in the general population, such as depression and anxiety, have conflicting data about their association with sickle cell disease. Concerning psychosis, the literature is even poorer, being composed mainly of case reports. Currently, two fields have been highlighted in the first episode of psychosis and schizophrenia literature: 1. The influence of environmental factors: research on this field in sickle cell disease becomes relevant once this disease has a chronic course with several psychosocial stressors. During childhood, hospitalizations for pain crises and other clinical complications related to disease are frequent. During adolescence, jaundice, enuresis, delayed physical maturation and growth could affect the social adjustment. Among adults, unemployment and reduced quality of life has been reported. 2. Neuroimaging studies: sickle cell disease patients have a high prevalence of stroke, reaching up to 11% in individuals until the age of 20 and 24% until the age of 45. : This is a case report of a first episode of psychosis in a 20 year old male with sickle cell disease. Results: Two weeks before the first assessment at the psychosis outpatient unit the patient was brought by his parents to the emergency ward because he believed that a television announcer was saying his name and addressing him directly. In addition, over the last 3 months prior to the first assessment he behaved as he had been stalked and couldn’t get out of his house by himself. He justified his behavior and fear based in a delusional thought that he offended a girl which lived near him and, because of that, the girl’s mother wanted to do him harm. In his previous history there are several environmental factors related to the sickle cell disease that can be seeing as a stressor to trigger psychotic symptoms in susceptible individuals. Among these factors, during childhood and adolescence, this patient had more than 15 hospitalizations due to sickle cell disease complications. He also has a symbiotic relationship with his overwhelming parents who have strong feelings of guilt related to the sickle cell disease. In school, this patient was a victim of bullying mainly due to his physical frailty and paleness. From the biological perspective, despite having an illness with high rates of central nervous system involvement, laboratory tests and MRI showed no changes that would justify the psychiatric condition. Over the last four months the patient has been taking antipsychotic and antidepressant medication with an improvement in the psychotic symptoms, allowing him to run daily arrows outside his house by himself. However, he still fears to be attacked and demonstrates a low criticism about the pathological symptoms. Discussion: Therefore, this report suggests that environmental factors related to sickle cell disease may contribute to the onset of psychosis in susceptible individuals.

Increased PLA2 activity in the hippocampus of patients with temporal lobe epilepsy and psychoses

Leda L. Talib1, Kette D. Valente1, Nadia R. B. Raposo1, Silvia Vincentiis1, Wagner F. Gattaz1

1Universidade de São Paulo, São Paulo, SP, Brasil

Background: The aim of this work was to investigate whether increased activity of the enzyme phospholipase A2 (PLA2) in the brain, as frequently reported in schizophrenia, is also related to psychosis in epilepsy. Our working hypothesis was based on the increased prevalence of schizophrenia-like psychosis in patients with temporal lobe epilepsy (TLE) secondary to mesial temporal sclerosis (MTS), as compared to patients with other forms of epilepsy. : We determined PLA2 activity in hippocampal tissue from 7 patients with TLE-MTS and psychosis, as compared to 9 TLE-MTS patients without psychosis. Hippocampal tissue was obtained from patients who underwent an anterior temporal lobectomy due to therapy-resistant epilepsy. Results: We found that patients with TLE-MTS and psychosis had a significantly increased calcium independent PLA2 activity as compared to patients without psychosis (p = 0.016). Discussion: Our finding suggest that an increment in brain PLA2 activity is not specific for schizophrenia, but rather may be associated to the manifestation of schizophrenia-like psychotic symptoms in general.

Effects of the putative antipsychotic alstonine on glutamate uptake and S100B secretion in hippocampal slices

Ana P. Herrmann1,2, Paula Lunardi2, Carlos A. Gonçalves2, Elaine Elisabetsky1,2

1Laboratório de Etnofarmacologia, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brasil/2Programa de Pós-Graduação em Ciências Biológicas: Bioquímica, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brasil

Background: It was after the introduction of chlorpromazine that the first pharmacological evidences were generated to associate the symptoms of schizophrenia to an enhanced dopaminergic transmission. Recently, however, glutamatergic dysfunction has gained a central role in the understanding of the neurobiology of schizophrenia: dopaminergic malfunctioning would be, in fact, the consequence of a primary deficit in glutamatergic transmission. In this context, glial-neuronal interactions emerge as a crucial aspect in the control of glutamate homeostasis, and a significant role has been assigned to glia in the pathophysiology of schizophrenia. Despite advances in the last decades, negative and cognitive symptoms remain poorly treated by current antipsychotics; innovation in drug discovery and development is thus sorely required. Alstonine is an alkaloid showing atypical antipsychotic-like properties in mouse models, present in plant preparations used in Nigeria by traditional psychiatrists to treat mentally ill patients. The aim of this study was to further characterize alstonine mechanism of action by evaluating its effects on glutamate uptake and S100B release in hippocampal slices. :
Hippocampi from 30-day-old rats were removed and sliced in 0.3 mm transverse sections. The slices were transferred to 24-well plates containing HEPES-buffered saline solution; the medium was changed every 15 min for 2 h at room temperature. Treatments (10 µM haloperidol, 10 and 100 µM clozapine or 1, 10 and 100 µM alstonine) were then added, and slices incubated for 1 h at 30°C. Samples of the medium were collected (10 µL) and kept in -20°C until S100B levels were determined by ELISA. Glutamate uptake assays were started with the addition of 0.1 mM l-glutamate and 0.66 µCi/mL l-[2,3-3H]-glutamate; incubation was stopped after 5 min by removing the medium and rinsing the slices twice with ice-cold solution. Slices were lysed in 0.5 N NaOH and the radioactivity measured in a scintillation counter. Cell viability and integrity were evaluated by the MTT assay and LDH activity, respectively. Data were analyzed by one-way ANOVA followed by SNK, with p < 0.05 set for significance. Results: S100B secretion was altered by antipsychotic treatments (F6,115 = 2.98, p < 0.01). Haloperidol (10 µM, p < 0.05) and clozapine (100 µM, p < 0.05) decreased extracellular S100B, while alstonine was devoid of effects. Glutamate uptake was significantly (F6,56 = 8.53, p < 0.0001) diminished by treatment with the atypical clozapine (100 µM, p < 0.001) and alstonine (10 and 100 µM, p < 0.01 and p < 0.001, respectively), while the typical haloperidol (10 µM) was devoid of effect. No significant alterations were observed for MTT (F6,53 = 2.15, p > 0.05) or LDH levels (F6,56 = 0.84, p > 0.05), indicating that cells were viable and intact. Discussion: S100B is an astrocytic protein indicative of astroglial function, involved in brain development and synapse formation, as well as dopaminergic and glutamatergic transmission. It has been documented that S100B levels are increased in plasma and cerebrospinal fluid of schizophrenic patients. We here observed that haloperidol and clozapine (but not alstonine) decreased S100B levels, consistent with previous data obtained with C6 and OLN-93 cell cultures, suggesting that these agents have a normalizing effect on S100B secretion. Glutamate uptake was decreased by clozapine and alstonine, but not by haloperidol, suggesting that improved glutamatergic function contributes to the therapeutic effects of these atypical antipsychotics. Additionally, the data indicate that antipsychotic-induced changes in glutamate uptake and S100B release may be mediated by distinct pathways. Support: CNPq.

Is serine racamase an indicator of schizophrenia?

Deepak Kumar1, Kaneez Fatima2

1International Centre for Chemical and Biological Sciences, Karachi, Sind, Pakistan/2PAP RSB Institute of Health Sciences, Brunei Darussalam, Brunei

Background: Schizophrenia is a brain disease that has distressed human kind since the beginning of the written history. Firm knowledge about this illness is limited to certain areas including cognitive, risk genes etc. Basic question remains unanswered about the diagnostic heterogeneity and tissue neurochemistry. Several lines of evidence focus on direct involvement of glutamergic system in the pathophysiology of psychosis. : The pilot study measured the difference between the plasma serine recemase level of normal and schizophrenic patients and estimated the D-isomers excreted in the urine using gas chromatography and Gas chromatography and mass selectivity (GCMS) respectively. Results: Plasma and urine samples of normal and schizophrenic patients from UAE shows that the level of serine recemase and D-serine respectively is lower in schizophrenic pateints than that of the normal subjects. Discussion: The hypofunction of the glutamate N-methyl-D-Aspartate receptor (NMDAR) has been proposed as a model of schizophrenia in humans using molecular marker and also due to evidence suggesting modulation of glutamate circuitries after antipsychotic administration. In this regard there is increasing evidence from pharmacological and genetic studies that suggest that D-serine an endogenous co agonist to the NMDA subtype glutamate receptor, may be implicated in schizophrenia (SCZ). Although an association of genes for D-serine degradation such as D-amino acid oxidase and G72 has been reported, a role of recemase in SCZ is unclear.

Randomized, double-blind, placebo-controlled trial of the nitric oxide donor sodium nitroprusside on the psychogenic symptoms induced by subanesthetic doses of (S)-ketamine in healthy volunteers

Tatiana M. N. Rezende1, Antônio W. Zuardi1,2, João Abrão1, João P. Machado-de-Sousa1, José A. Crippa1,2, Glen B. Baker3, Jaime E. C. Hallak1,2


1Universidade de São Paulo, Ribeirão Preto, SP, Brasil/2National Scienceand Tecnology Institute " Translational Medicine " CNPq, Ribeirão Preto, SP, Brasil/3University of Alberta, Edmonton, Alberta, Canada

Background: The use of subanesthetic doses of ketamine, an antagonist of N-methyl-D-aspartate glutamate receptors, is regarded as the best experimental model to induce psychotic symptoms in healthy volunteers that mimic the positive, negative, and cognitive syndromes of schizophrenia. : Thirty healthy volunteers aged 18-45 years were assigned to three groups, which received 0.15, 0.25, or 0.5 mcg/kg/min intravenous sodium nitroprusside for 60 min and a standardized dose of ketamine (1-min bolus of 0.26 mcg/kig/min followed by an infusion of 0.25 mcg/kg/min for 60 min). Participants were assessed with the Brief Psychiatric Rating Scale (BPRS), the Clinician Administered Dissociative States Scale (CADSS) and a set of cognitive tests (FAS, 2-back, and Stroop Color Word Test). The scales were applied at baseline, after bolus infusion, and at the end of the infusion. The cognitive tests were performed at baseline and +60 min. Results: The administration of sodium nitroprusside was associated with lower scores in the BPRS compared to placebo in the post-bolus and final phases of the trial. The subjective version of the CADSS demonstrated an effect of phase, but not of the phase-drug interaction or of the dose of sodium nitroprusside. The analysis of the objective version of the CADSS showed effects of phase and drug, with the administration of sodium nitroprusside associated with smaller increases in post-bolus scores in relation to baseline than placebo. Concerning the cognitive measures, the administration of sodium nitroprusside was connected with a better performance in the verbal fluency task compared to placebo. Discussion: The administration of sodium nitroprusside had clear effects in controlling psychogenic symptoms induced by the administration of ketamine, as assessed using two scales that measure distinct psychopathological dimensions. Also, the administration of sodium nitroprusside was also associated with a reversal of ketamine-induced cognitive impairments, improving performance in a verbal fluency task.


Imaging genetics: new perspectives for understanding schizophrenia


Lucas Renno Vinicius1, Fernando M. V. Dias1,2

1Universidade Federal de Viçosa, Viçosa, MG, Brasil/2Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brasil


Background: Imaging genetics provides a unique tool with which to explore and evaluate the functional impact of brain-relevant genetic polymorphisms with the potential to understand their impact on behavior. Although studies have already identified several genotypes related to schizophrenia, there is a need to understand the relationship between these genotypes, environmental risk factors and the real consequences for the neuronal network. Integrating genotypic information with brain imaging results can help identifying the role of candidate genes at the level of brain function in people with the disease or with some vulnerability to develop it. The purpose of the present work was to review existing data of literature on imaging genetics and schizophrenia. : The study was done through a systematic review of the literature. Studies with original data were identified via searching electronic database in PubMed and Lilacs using the key words schizophrenia and imaging genetics. All original articles were included. Results: Twenty-eight eligible studies were identified. Among those, ten studies provided comparative data from patients with the disease and healthy volunteers. The other eighteen studies evaluated subjects with genotypes related to schizophrenia or persons with high genetic risk, like first degree relatives of patients, and compared with the healthy control group. The methods of image acquisition and processing used can be quantified magnetic resonance imaging in sixteen studies (five of these studies also used voxel-based morphometry) and functional magnetic resonance in twelve. The main genes or genotypes involved were 22q 11 deletion, ZNF804A risk allele, COMT, Prion Protein (PRNP), Neureglin 1, VNTR allele 2, DISC 1, DTNBP1, CACNA1C and G72. Discussion: Anatomical abnormalities of the brain in schizophrenia patients and subjects with genetic high risk were confirmed using structural imaging. Some alterations like lateralization, deformities and volumetric deficits were found in amygdale, frontal gyrus, gray matter, hippocampal and prefrontal lobes. More than that, specific cognitive functions and emotion regulation were impaired according to some genotypes and elucidated by functional neuroimage. Therefore, these data showed genetic correlations with specific mode of network operation that successfully discriminated schizophrenia patients from control population. Moreover, different patterns of premorbid structural deficits and associated changes in function can be identified between those who go on to develop schizophrenia from those do not. In conclusion, schizophrenia likely involves different abnormal brain maturational processes which are genetically determinate and modulated by environment, some occurring in early neurodevelopment while others manifest during adolescence and early adulthood closer to illness onset.   

Drug treatment dependent GSK3B expression in schizophrenic patients

Daniel S. Kerr1, Leda L. Talib1, Martinus T. van de Bilt1, Aline S. Ferreira1, Wagner F. Gattaz1

1Instituto de Psiquiatria, Laboratório de Neurociências (LIM27), Faculdade de Medicina da Universidade de São Paulo, São Paulo, SP, Brasil

Background: Glycogen synthase kinase-3B (GSK3B) seems to play a central role in several biochemical pathways in the central nervous system. Alterations in GSK3B have been linked to many psychiatric disorders, such as Alzheimer disease, bipolar disorder and schizophrenia. The first associations with schizophrenia showed that patients presented a decrease in GSK3B mRNA levels in postmortem brain samples. Also, there was a reduction of cerebrospinal fluid levels of GSK3B protein. Contradictory results have arisen since then. However, studies of GSK3B related pathways, such as Wnt and dopaminergic system, support a role for GSK3B in the pathophysiology of schizophrenia. We aimed here to investigate GSK3B mRNA expression levels in schizophrenic patients who were on three different treatments, Clozapine (CLZ), Olanzapine (OLA) and Haloperidol (H). We also compared them to the GSK3B expression levels of healthy controls (CTR). : Patients for this study were recruited at the Institute of Psychiatry of the Faculty of Medicine, Universidade de São Paulo. The sample comprised 5 patients on CLZ, 5 on OLA and 6 on H treatments, as well as 6 healthy controls. Blood samples were collected after fasting for at least 8h. Collection and mRNA extraction followed the PAXGENE manufacturers' protocol. mRNA quality was accessed by agarose electrophoresis and spectrophotometry. cDNA was synthesized by reverse transcription with oligo dT primer. Amplification of each sample was monitored by real-time PCR. Normalized relative quantification was calculated comparing the amplification of GSK3B with 3 reference genes (ACTB, B2M and GSTP1). Results: GSK3B expression was significantly higher in the CLZ and OLA group when compared to the H group (p = 0.021 and p = 0.010 respectively, ANOVA with post hoc Bonferroni test). No difference was observed when comparing GSK3B expression in CLZ, OLA and H groups with CTR. Discussion: There are evidences pointing to a decrease of GSK3B expression associated with schizophrenia. Here we show patients chronically treated with clozapine and olanzapine had a higher expression level of GSK3B mRNA when compared to those treated with haloperidol. This result might help elucidate the different mechanisms by which the abovementioned treatments exert their effects.

The antipsychotic-like effects of the alkaloid alstonine are mediated by 5HT2A/C receptors

Viviane M. Linck1,2, Marília M. Bessa1, Ana P. Herrmann1,2, Christopher O. Okunji3, Elaine Elisabetsky1,2


1Laboratório de Etnofarmacologia, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brasil/2Programa de Pós-Graduação em Ciências Biológicas: Bioquímica, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brasil/3International Centre for Ethno Medicine and Drug Discovery, Nsukka, Enugu State, Nigeria

Background: Improvement in the management of schizophrenia is dependent on innovation in the area of antipsychotic medication, especially regarding innovative mechanism of action. Alstonine is an alkaloid present in plant species traditionally used in Nigeria to treat mental illnesses. Though asltonine mechanism of action remains unclear it clearly shows an antipsychotic profile in various mouse models, yet with differences from known antipsychotics. Importantly, D2 dopamine receptor blockade does not seem significant for alstonine antipsychotics-like effects, whereas evidence points to 5HT2A/C inverse agonist associated with its anxiolytic properties. The aim of this study is to examine the role of 5HT2A/C receptors in the antipsychotic-like effects of alstonine. We analyzed the effects of ritanserin (5HT2A/C antagonist) on mouse models associated with positive, negative and cognitive symptoms. : MK801-induced hyperlocomotion (HL): Mice were treated i.p. with saline or ritanserin (0.1 mg/kg), and 10 min later with saline or alstonine (1.0 mg/kg); 30 min later mice were treated with MK801 (0.3 mg/kg) and after 30 min placed in activity cages. Locomotion was automatically recorded for 10 min. MK801-induced social withdrawal (SW): 48 and 24 h before testing mice were submitted to 10 min adaptation sessions in the test box. At test day mice were randomly paired to an unfamiliar partner of the same treatment group and the time spent in social interaction was video recorded for 10 min (Noldus). Mice were treated with saline or ritanserin (0.1 mg/kg), 10 min later with saline or alstonine (1 mg/kg), and 30 min later with saline or MK801 (0.3 mg/kg). The social interaction test was performed 30 min after the last treatment. MK801-induced Working Memory Deficit (WMD): The step-down inhibitory avoidance test was used. The apparatus was an acrylic box with a platform fixed in the center of the grid floor; each mouse was placed on the platform and the latency to step-down was automatically recorded in training and test sessions. In the training session, mouse received a 5 s 0.3 mA foot shock upon stepping down; test sessions were performed 10 s after training. Animals were treated with saline or ritanserin (0.1 mg/kg), 10 min later with saline or alstonine (1 mg/kg), and 30 min later with saline or MK801 (0.05 mg/kg). Statistics: HP and SW were analyzed by 2-way ANOVA/SNK, and WMD by Kruskal-Wallis/Mann-Whitney/Willcoxon. Results: Hyperlocomotion: a significant interaction (F2,54 = 3.43; p = 0.039) indicates that ritanserin alters the preventive effect of alstonine, which is confirmed by SNK. Social withdrawal: though interaction was not identified by 2-way ANOVA, SNK showed that ritanserin blocked (p = 0.05) the preventive effects of alstonine. Memory Deficit: data likewise shows that pretreatment with ritanserin abolishes (Wilcoxon, p = 0.13) the alstonine preventive effects. Discussion: In agreement with our prior suggestions of 5HT2A/C receptor involvement in the mechanism of action of alstonine, we here show that these receptors are critically involved in alstonine antipsychotic-like effects on mouse models of cognitive deficit, positive and negative schizophrenia symptoms. Accordingly, serotonergic modulation by atypical antipsychotics is thought to be crucial for the purported advantages of these medications over older agents. Though a definitive characterization of the nature of alstonine interaction with serotonin receptors subtypes is warranted, the antipsychotic properties brought up by serotonin modulation not associated with dopamine receptor blockade may reveal a novel mechanism of action of interest to develop new antipsychotic medication. Support: CNPq (490493/2008-4).

ZDHHC8 Variants are associated with age at onset of schizophrenia

Letícia N. Spíndola1,2, Vanessa K. Ota1,2, Ary Gadelha2,3,4, Fernanda T. Bellucco1,2, Denise M. Christofolini1, Marcso L. Santoro1,2, Vinícius C. Mrad1,2, Aírton F. Filho2,3,4, Jair J. Mari4, Maria I. Melaragno1, Marilia A. Smith1, Rodrigo A. Bressan2,3,4, Sintia N. Belangero1,2

1Divisão de Genética, Departamento de Morfologia e Genética, Universidade Federal de São Paulo, São Paulo, SP, Brasil/ 2Laboratório Interdisciplinar de Neurociências Clínicas (LiNC), São Paulo, SP, Brasil/3Programa de Esquizofrenia (PROESQ), Departamento de Psiquiatria, Universidade Federal de São Paulo, São Paulo, SP, Brasil/4Departamento de Psiquiatria, Universidade Federal de São Paulo, São Paulo, SP, Brasil

Background: Several studies have shown that age at onset has an impact on clinical manifestations and neuropsychological profile of schizophrenia. One known genetic risk for this disease is the 22q11.2 deletion, where ZDHHC8 gene is located. ZDHHC8 gene encodes a putative palmitoyltransferase enzyme and some polymorphisms, including rs175174 (A/G), were associated to schizophrenia in different populations. The aim of this study was to evaluate the association of ZDHHC8 rs175174 polymorphism with schizophrenia and also with age at onset of the disease. : A total of 187 patients with schizophrenia and 199 healthy controls were recruited from the PROESQ (Programa de Assistência à Esquizofrenia) and LiNC (Laboratório Interdisciplinar de Neurociências Clínicas) of Unifesp. Each patient was assessed and diagnosed by two psychiatrists according to DSM-IV and genotyped for rs175174 polymorphism by TaqMan probe-based real-time PCR assay. One-hundred and thirty seven patients were selected and divided into two groups according to age at onset (Group I: < 18 years; Group II: ≥ 18 years). Logistic regression analyses were applied to verify association of this polymorphism with schizophrenia and with age at onset. Results: Genotype frequency distribution of rs175174 polymorphism did not deviate from Hardy-Weinberg equilibrium. The G allele frequency in patient group was 42.25% and in control group was 43.22%. No association between genotype and schizophrenia was found (p = 0.218). However, AG-genotype carriers were less frequent in Group I (age at onset < 18 years) than AA-genotype carriers (p = 0.035; OR = 0.33; CI95% = 0.12-0.93) and GG-genotype carriers (p = 0.007; OR = 0.22; CI95% = 0.07-0.67). Discussion: AG-genotype seems to be a protective factor for early-onset schizophrenia, though no association to the disease was found. It is worthy of note that the minor allele frequency is different in distinct populations and this study is the first that investigated this polymorphism in a Brazilian population. ZDHHC8 rs175174 polymorphism regulates the level of fully functional transcript by modulating the retention of intron 4 of the gene ZDHHC8. Therefore, considering these results and ours, it would be interesting to investigate the role of ZDHHC8 in other phenotypes, such as cognition and brain morphology. Studying this polymorphism in age at onset of schizophrenia may be important to identify predictive factors for a more severe manifestation of the disease, providing an earlier and better intervention. Financial support: FAPESP, Brazil.

Apolipoprotein E gene and schizophrenia in Medellin, Colombia: a case-cohort study

Juan C. Arango-Viana1, Jenny Garcia-Valencia1, Ana V. Valencia-Duarte1, Ana L. Paez-Vila1, Manuel J. Castilla1

1Universidad de Antioquia, Medellín, Antioquia, Columbia

Background: Several studies have reported an association between schizophrenia and Apolipoprotein E gene, specifically to Epsilon 4 allele. However, this has not been consistently found in different populations. We evaluated the association between Apolipoprotein alleles and schizophrenia in Medellin, Colombia. : A case-cohort study was done, taking as cases subjects with schizophrenia according to DSM-IV-TR criteria. The comparison cohort was a probabilistic sample from Medellin, Colombia. We estimated ratio of incidence proportions, population attributable risk and hazard ratio using the onset-age of schizophrenia. Results: We evaluated 300 subjects with schizophrenia and a representative sample from Medellin consisting of 854 individuals. Allelic and genotypic frequencies were in Hardy-Weinberg equilibrium. We estimated ratio of incidence proportions, population-attributable risk and hazard ratios. Discussion: Results will be discussed. 


Evidences of an interaction between the CNR1 and the DGCR2 genes influencing the etiology of schizophrenia

Vinicius C. Mrad1,2, Aírton F. S. Filho2,3,4, Ary Gadelha2,3,4, Vanessa K. Ota1,2, Marcos L. Santoro1,2, Fernanda T. S. Bellucco1, Letícia M. N. Spíndola1,2, Deyvis M. L. V. Rocha2,3,4, Denise M. Christofolini1, Jair J. Mari4, Maria I. Melaragno1, Marília A. C. Smith1, Rodrigo A. Bressan2,3,4, Sintia I. N. Belangero1,2

1Divisão de Genética, Departamento de Morfologia e Genética, Universidade Federal de São Paulo, São Paulo, SP, Brasil/2 Laboratório Interdisciplinar de Neurociências Clínicas (LiNC), São Paulo, SP, Brasil/3Programa de Esquizofrenia (PROESQ), Departamento de Psiquiatria, Universidade Federal de São Paulo, São Paulo, SP, Brasil/4Departamento de Psiquiatria, Universidade Federal de São Paulo, São Paulo, SP, Brasil


Background: The pathophysiology of schizophrenia apparently involves a complex interaction between genetic vulnerabilities and environmental risk factors. Cannabis use has been considered one of these factors that may contribute with the emergence of psychotic symptoms in genetic predisposed individuals and worsens the course of pre-established disease. The endocannabinoid system is involved in this process and probably has implications in the psychopathology of the psychotic episode. The CNR1 gene, that encodes the cannabinoid receptor 1 (CB1), is located on chromosome 6q14-15, which has been considered as a susceptibility locus for schizophrenia. Other important locus associated with this disease is on chromosome 22q11.2, that includes several genes related with schizophrenia as the DGCR2 (DiGeorge syndrome critical region gene 2), that is an adherence receptor protein coding. We aimed to investigate the interaction between CNR1 and DGCR2 and its influence on the etiology of schizophrenia. : We recruited 187 patients with schizophrenia and 221 healthy controls from the PROESQ (Programa de Assistência à Esquizofrenia) and LiNC (Laboratório Interdisciplinar de Neurociências Clínicas) of Unifesp. Each patient was assessed and diagnosed by two psychiatrists according to DSM-IV and genotyped for the polymorphisms rs806380 (A/G) of the CNR1 gene and the rs2073776 (T/C) of the DGCR2 gene by real time PCR with Taqman detection. It was correlated to schizophrenia diagnosis and other variables such as cannabis use. Population stratification analysis was made from genetic markers chosen for the Brazilian population in order to correct for statistical confounding factors related to ethnic differences. Statistical analyses were performed using a SPSS computer program. Results: We found a significant association between the interaction of the CNR1 and DGCR2 polymorphisms and schizophrenia etiology, although we did not find an association between schizophrenia and the polymorphisms individually (CNR1 p = 0.683; DGCR2 p = 0.318). The CNR1 AG-genotype carriers associated with the DGCR2 TT-genotype carriers were more frequent than the CNR1 GG-genotype carriers associated with the DGCR2 CC-genotype carriers in schizophrenia patients (p = 0.011; OR = 3.365). We did not find any sort of association with cannabis use. Discussion: These results suggest an interaction between CNR1 and DGCR2, which the CNR1 AG-genotype and the DGCR2 TT-genotype may play as a risk factor for schizophrenia. The association between two polymorphisms of these genes seems to play an important role in the pathophysiology of schizophrenia, however further studies in different populations are required. Financial Support: FAPESP, Brazil.

A novel PRODH mutation in a patient with schizophrenia

Fernanda T. Bellucco1, Ary Gadella2,3, Vanessa K. Ota1,2, Denise M. Christofolini1, Marcos L. Santoro1,2, Airton F. S. Filho2,3, Jair J. Mari3, Marilia A. C. Smith1, Rodrigo A. Bressan2,3, Sintia I. Belangero1,2, Maria I. Melaragno1


1Divisão de Genética, Departamento de Morfologia e Genética, Universidade Federal de São Paulo, São Paulo, SP, Brasil/2Laboratório Interdisciplinar de Neurociências Clínicas (LiNC), Universidade Federal de São Paulo, São Paulo, SP, Brasil/3Departamento de Psiquiatria, Universidade Federal de São Paulo, São Paulo, SP, Brasil

Background: Schizophrenia is a common and severe mental illness that affects 0.3%-1.6% of the general population. Several studies have shown that 22q11 deletion is an important risk factor for schizophrenia. Multiple studies in human and mouse models suggest that PRODH polymorphisms are risk factors for schizophrenia, although their role in the pathogenesis is not clear. The PRODH gene, that is located in 22q11.2 region, encodes proline oxidase (POX) that degrades proline to Δ1-pirolina-5-carboxilato (P5C). POX is an inner mitochondrial membrane enzyme expressed in kidney, liver and brain. Many studies suggest that alterations in this pathway, caused by mutations that inactivate the PRODH gene, results in reduction of POX activity, contributing to the risk for schizophrenia. We report a patient with schizophrenia who presents a novel mutation in PRODH gene. : This patient was assessed and diagnosed according to DSM-IV. We studied 16 polymorphisms of the PRODH gene using Real Time PCR detection system with Taqman', Restriction Fragment Length Polymorphism (RFLP) and gene sequencing. Plasma proline level was determined in the morning after overnight fasting.
Results: During the sequencing of exon 12 we identified a substitution of a cytosine by an adenine at position 1292 in PRODH gene (C1292A). This change has not been previously described in the literature and results in a substitution of aspartic acid for a glutamate (D426E). In this patient, the dosage of plasma proline was elevated (427mmol/L) characterizing a hyperhiprolinemia. In addition, we found in this patient a R431H functional polymorphism (rs2904552) in heterozygosity that is associated with a moderate reduction (30% to 70%) in POX activity. Discussion: We found a novel mutation in PRODH gene that could be related to altered proline level and with schizophrenia Brazilian patient. Probably, this mutation should influence alone or in combination with the R431H polymorphism on proline plasma level in this patient. However, a functional study of this mutation is necessary to define how it would interfere in the POX activity and consequently in plasma proline levels and also to establish its relationship to schizophrenia.

Evidences of an interaction between the CNR1 and the DGCR2 genes influencing the antipsychotics treatment response in schizophrenia


Airton F. Santos Filho1,2,3, Vinícius C. Mrad1,4, Ary Gadelha1,2,3, Vanessa K. Ota1,4, Marcos L. Santoro1,4, Fernanda T. Bellucco4, Letícia M. Spíndola1,4, Deyvis M. Rocha1,2,3, Denise M. Christofolini4, Jair J. Mari3, Maria Isabel Melaragno4, Marilia A. Smith4, Rodrigo A. Bressan1,2,3, Sintia I. Belangero1,4

1Laboratório Interdisciplinar de Neurociências Clínicas (LiNC), São Paulo, SP, Brasil/2Programa de Esquizofrenia (PROESQ), Departamento de Psiquiatria, Universidade Federal de São Paulo, São Paulo, SP, Brasil/3Departamento de Psiquiatria, Universidade Federal de São Paulo, São Paulo, SP, Brasil/4Divisão de Genética, Departamento de Morfologia e Genética, Universidade Federal de São Paulo, São Paulo, SP, Brasil

Background: The pathophysiology of schizophrenia apparently involves a complex interaction between genetic vulnerabilities and environmental risk factors. Cannabis use has been considered one of these factors that may contribute with the emergence of psychotic symptoms in genetic predisposed individuals and worsens the course of pre-established disease. The endocannabinoid system is involved in this process and probably has implications not only in psychopathology of this disease, but also in the pharmacological response to antipsychotic drugs. The CNR1 gene, that encodes the cannabinoid receptor 1 (CB1), is located on chromosome 6q14-15, which has been considered a susceptibility locus for schizophrenia. Other important locus associated with this disease is on chromosome 22q11.2, which includes several genes related with schizophrenia as the DGCR2 (DiGeorge syndrome critical region gene 2) that is an adherence receptor protein coding. A study have showed that this gene seem to be involved with antipsychotic metabolism. We aimed to investigate the interaction between CNR1 and DGCR2 and its influence on treatment response. : 143 patients with schizophrenia (71 refractory and 72 non refractory patients) were recruited from the PROESQ (Programa de Assistência à Esquizofrenia). Each patient was assessed and diagnosed by two psychiatrists according to DSM-IV and genotyped for the polymorphisms rs806380 (A/G) of the CNR1 gene and the rs807759 (A/G) of the DGCR2 gene by real time PCR with detection Taqman. It was correlated to the treatment refractoriness and cannabis use. Population stratification analysis was made from genetic markers chosen for the Brazilian population in order to correct statistical confounding factors related to ethnic differences. Statistical analyses were performed using SPSS computer program. Results: We found a significant association between the interaction of the CNR1 and DGCR2 polymorphisms and the treatment refractoriness, although there was not an association between refractoriness or the cannabis use and the polymorphisms individually. The CNR1 AG-genotype carriers associated with the DGCR2 AA-genotype carriers were more frequent than the CNR1 GG-genotype carriers associated with the DGCR2 GG-genotype carriers in non-refractory patients (p = 0,018; OR = 0,249). We did not found any kind of association with the cannabis use. Discussion: These results showed an interaction between CNR1 and DGCR2 genes, where AG-genotype associated with AA-genotype, respectively, seem as a protection factor for antipsychotics refractoriness. Our data suggest these genes seem to play an important role on treatment response and they could be prediction factors in the pharmacogenomics. Thus, it would be interest to investigate these two genes even more in order to unravel the action mechanism of antipsychotics in the brain.

Treatment-resistant schizophrenia in a patient with mega cisterna magna: case report

Daniel Almeida Prado1, Joao Paulo Machado de Souza1, David Araujo1, Silvio L. Moraes1, Antonio W. Zuardi1, Antonio E. Nardi2, Jose A. S. Crippa1, Jaime E. C. Hallak1

1Departamento de Neurociências e Ciências do Comportamento, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, SP, Brasil/2Laboratório do Pânico e Respiração, Instituto de Psiquiatria, Universidade Federal do Rio de Janeiro (UFRJ), Rio de Janeiro, RJ, Brasil

Background: This report describes a case of treatment-resistant schizophrenia in a patient with mega cisterna magna and the response to clozapine treatment. This clinical observation lends further support to the current notion that the presence of neurodevelopmental conditions in schizophrenia is associated with better response to clozapine treatment. : A literature review was performed using the key words "Mega Cisterna Magna" and "Schizophrenia", dating from 1975 to 2011. A case report on mega cisterna magna in a patient suffering from treatment-resistant schizophrenia is described. Results: The treatment of this refractory case with clozapine proved fairly successful, highlighting about the necessity of studies that systematically correlate neurodevelopmental alterations and improved response to clozapine in treatment-resistant schizophrenia. Discussion: Our findings suggest that mega cisterna magna may be one of the neurodevelopmental abnormalities associated with treatment-resistant schizophrenia, and supports the notion that clozapine may be more effective in the presence of such alterations.

Nodular neoplasia in the left temporal lobe in an adolescent with psychotic symptoms

Bruno Lima1,2, Dalton Roston1,2, Luiz H. Dieckmann1,2, Paula Ramalho1,2, Ary Gadelha1,2, Rodrigo Bressan1,2

1Programa de Esquizofrenia (PROESQ), São Paulo, SP, Brasil/2Universidade Federal de São Paulo, São Paulo, SP, Brasil

Background: The initial syndromic approach has been used due to a variety of psychiatric conditions that evolve with psychotic symptoms. This facilitates the differential diagnosis, mainly when there is suspicion of a possible organic etiology. The aim of this presentation is discussing a case of an adolescent in her first psychotic episode, where the clinical examination did not indicate risk of neurologic lesion and a brain magnetic resonance (MR) scan revealed a nodular neoplasia in the left temporal lobe. : Case report: YDF, a 17-year-old female high school was referred for outpatient treatment after an episode of agitation, anxiety and bewilderment. First assessment: delusions of reference and mild affective and volitional impairment (PANSS = 74 pts). Background: normal delivery at term without complications, normal neurodevelopment without learning difficulties or school failure. Her premorbid personality was marked by introversion, excessive shyness and restricted socialization. There is no history of psychosis in the family. Results: Clinical history: At 10-years-old, she developed a progressive social isolation, and monthly, had bizarre ideas of introduction of thoughts and feeling that there were "cameras filming in her bedroom". These symptoms were mild and she maintained a good academic performance. A year ago, however, there was the beginning of the delusions of reference, which became daily in the past six months, with significant functional impairment. Because of the delusions, she gradually stopped going out alone and did not attend the school regularly anymore. There was also anhedonia, hypobulia and inappropriate affect. There was no hallucinatory behavior. Physical and neurological examinations were normal, such as general blood tests and electroencephalogram. A brain MR scan revealed a nodular lesion in the left temporal lobe, which had an indication of neurosurgery. We prescribed risperidone 2 mg/day with modest clinical response for the psychotic symptoms after 8 weeks (PANSS = 58 pts), when she underwent neurosurgery, with no complications. A month later, however, there is no remission of the psychotic symptoms, and then she follows in use of risperidone 3 mg/day (PANSS = 52 pts). Discussion: The American Academy of Child and Adolescence Psychiatry does not indicate a brain MR scan as mandatory test in the first psychotic episode in adolescents. However, there is no consensus on the subject, therefore, that possibility should be considered in atypical presentations or changes in screening tests.

Cortical thickness reduction in frontal lobe is associated with duration of illness in schizophrenia

Idaiane Batista de Assunção1,2, Ary Gadelha1,2,3, Vanessa Kiyomi Ota2,4, Sintia Iole Nogueira Belangero2,4, Denise Maria Christofolini4, Fernanda Teixeira da Bellucco4, Jair de Jesus Mari1, Maria Isabel Melaragno4, Marilia de Arruda C. Smith4, Rodrigo Affonseca Bressan1,2,3, Andrea Parolin Jackowski1,2

1Departamento de Psiquiatria, Universidade Federal de São Paulo, São Paulo, SP, Brasil/2Laboratório Interdisciplinar de Neurociências Clínicas (LiNC), São Paulo, SP, Brasil/3Programa de Esquizofrenia (PROESQ), Departamento de Psiquiatria, Universidade Federal de São Paulo, São Paulo, SP, Brasil/4Divisão de Genética, Departamento de Morfologia e Genética, Universidade Federal de São Paulo, São Paulo, SP, Brasil

Background: Previous studies have shown cortical volume loss in frontotemporal regions in schizophrenic patients and that these reductions may correlate with disease symptoms and cognitive deficits. A matter of debate is whether this volume reduction occurs before or after the onset of disease. The aim of the study was investigate possible cortical thickness changes in frontotemporal regions in relation to age onset and duration of illness. : A group of 157 patients (103 males, age range from 16-65 years-old) diagnosed with schizophrenia, according to DSM-IV criteria, was enrolled in this study. Subjects were recruited from the Schizophrenia Program (PROESQ) at Federal University of São Paulo (Unifesp) and underwent a MRI scan in a 1.5T MAGNETON Sonata Siemens scanner. Cortical segmentation was performed using FreeSurfer 5.0. Statistical analysis was performed using the QDEC tool in the FreeSurfer software suite using a General Linear Model. Results were corrected for multiple comparions using Montecarlo simulation, p < 0.05. Results: One hundred and eighteen patients were able to conclude the MRI scan (82 males, age range from 16-63 years-old), with age of onset range from 14-41 years old. Results indicate a negative correlation between superior frontal, middle frontal gyrus, and left medial orbitofrontal cortical thickness and duration of illness in patients with schizophrenia. No significant correlation between frontotemporal cortical thickness and age of onset was observed for the patients. Discussion: Our findings suggest that deficits in brain volume observed in schizophrenic patients might be more related to duration of illness than age of onset, thus reinforcing a role for neurodegenerative processes after the diagnosis.

Longitudinal investigation of corpus callosum volume changes in first-episode psychosis


Tiffany M. Chaim1, Maristela S. Schaufelberger1, Fábio L. S. Duran1, Luciana C. Santos1, Pedro G. P. Rosa1, Marcia Scazufca1, Paulo R. Menezes2, Geraldo F. Busatto1

1Departamento de Psiquiatria, Faculdade de Medicina da Universidade de São Paulo, São Paulo, SP, Brasil/2Departamento de Medicina Preventiva e Seção de Epidemiologia, Faculdade de Medicina da Universidade de São Paulo, São Paulo, SP, Brasil

Background: Abnormalities of the corpus callosum have been shown in early stages of schizophrenia in several neuroimaging studies. There is strong evidence that these alterations are anatomical mediators of dysfunctional inter-hemispheric transfer in schizophrenia. However, studies are not consistent in demonstrating if these abnormalities are the result of a fixed neurodevelopmental abnormality or if they are caused by a progressive neurodegenerative process. Recent findings have reinforced both hypotheses. The present study aimed at determining if: (I) first episode psychosis patients would exhibit more pronounced brain volumetric changes than controls over a mean follow-up period of approximately 16 months; and (II) illness course/treatment would be related to these changes. : Magnetic resonance imaging was performed in 39 patients with first episode psychosis (first-episode schizophrenia or schizophreniform disorder -" FESZ) close to psychosis onset and 52 non-psychotic controls, and the samples were re-examined after a mean of 16 months (SD = 6) of follow-up. Longitudinal between-group differences in regional corpus callosum (CC) volume were investigated in a voxel-based morphometry (VBM) comparison. The CC was circumscribed with the MRIcro 1.39 program and divided into three subregions (anterior, medial, and posterior). Repeated-measures analyses of covariance (ANCOVA) of regional CC differences were conducted using the general linear model, with group and time as factors; and gender as a covariate when groups showed statistically significant difference for this variable. Results: There were no significant longitudinal volumetric reductions in CC volumes either in subjects with first-episode psychosis or in the control group. Longitudinal sub-group comparisons of FESZ patients according to the disease course (remitted versus non-remitted at follow-up) and antipsychotic exposure (treated versus untreated over the follow-up period) did not reveal any significant volume changes in the CC either. Discussion: Our findings do not support the hypothesis of CC volume changes indicating a progressive course of this white matter structure over the first years during the course of schizophrenia. However, although our baseline brain scans were acquired close after the onset of the disease, we cannot rule out the possibility that progressive CC changes would have already occurred maximally before that, for instance in prodromal phases of the disorder.

Effects of minocycline on brain morphometry in schizophrenia: a voxel-based morphometry study

Cristiano Chaves1, Cristiane R. Marque1, João P. Maia-de-Oliveira1, Thiago B. Ferreira1, Antonio C. Santos1, David Araujo1, Rodrigo A. Bressan2, Andrea P. Jackowski2, João P. Machado-de-Sousa1, José A. Crippa1,3, Antonio W. Zuardi1,3, Glen B. Baker3,4, Serdar M. Dursun3,4, Jaime E. Hallak1,3


1Universidade de São Paulo, Ribeirão Preto, SP, Brasil/2Universidade Federal de São Paulo, São Paulo, SP, Brasil/3INCT-TM, Brasil/4University of Alberta, Edmonton, Alberta, Canada

Background: Minocycline is an antibiotic of the tetracycline group with growing evidence of neuroprotection in various neurological disorders and can potentially optimize antipsychotic treatment of schizophrenia. Researches carried out with schizophrenia and other psychiatric disorders have shown that brain morphology may be partially related to the effects of psychotropic medication. In addition, the exact mechanisms of minocycline action in the central nervous system are unknown and have not been studied by neuroimaging. The aim of this study is to investigate the effects of minocycline on brain morphology in patients with schizophrenia after twelve months of a double-blind, placebo-controlled trial of minocycline added to treatment as usual. : This study included 24 outpatients with DSM-IV diagnosis of schizophrenia in their first five years of disease and on stable antipsychotic dose for at least four weeks and without relevant medical conditions. The patients were followed for 12 months and were evaluated by PANSS and CGI. The subjects were randomized to minocycline (200 mg/d) or placebo. There was careful matching of confounding parameters that may interfere with the course of schizophrenia and brain morphology, such as age, length of education, duration of illness, duration of untreated psychosis, gender, diagnostic subtype and type of antipsychotic in use. Brain MRI images were analysed by voxel-based morphometry (VBM). Results: Patients in use of minocycline showed significant improvement in the CGI score, in the PANSS total score and in the PANSS subscales (positive, negative and general psychopathology) scores. There were no differences in the placebo group. VBM analysis showed that patients in the placebo group had significant reduction of gray matter volume in left prefrontal cortex (BA6) and in left posterior cingulate cortex (BA24) in comparison to the patients in the minocycline group. Discussion: Previous evidence have pointed out that structural brain abnormalities, including prefrontal cortex and posterior cingulate cortex, may be already present in the first episode or even before the onset of psychosis, with further deterioration in patients with poor clinical outcome or chronic course. In this study, the adjuvant treatment with minocycline showed improvement in both positive and negative symptoms of patients with recent-onset schizophrenia. Some studies have indicated that posterior cingulate gray matter volume may negatively correlate with positive symptoms and these findings may be related to the effects of minocycline on positive symptoms observed in this study. Similarly, the effectiveness of minocycline on negative symptoms may be related to the differences of prefrontal cortex gray matter volumes observed in the two groups. In addition, the effects of minocycline may have been mediated by modulation of microglia, by anti-apoptotic action and by protection against glutamate induced injury through the involvement in signaling cascades. The effectiveness of minocycline adjuvant treatment and its effects on brain morphology warrant further investigation.

Statistical discriminant analysis and automatic segmentation of the most significant changes: application to neuroimaging of schizophrenia

Paulo E. Santos1, Carlos E. Thomaz1, Danilo Santos1, Rodolpho Freire1, João R. Sato2, Mario R. Louzã3, Paulo C. Sallet3,
Geraldo Busatto4, Wagner F. Gattaz4

1Centro Universitário da Fundação Educacional Inaciana (FEI), São Bernardo do Campo, SP, Brasil/2Universidade Federal do ABC, Santo André, SP, Brasil/3Instituto de Psiquiatria do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo, SP, Brasil/4Departamento de Psiquiatria da Faculdade de Medicina da Universidade de São Paulo, São Paulo, SP, Brasi
l

Background: Schizophrenia is associated with structural and functional brain abnormalities, mainly in prefrontal and temporal lobes, these findings being largely detected due to recent advances in magnetic resonance imaging (MRI) techniques. We propose an integrated framework for extracting and describing patterns of disorders from medical images using a combination of linear discriminant analysis and active contour models and apply it to a set of images of patients with schizophrenia and healthy controls. : A multivariate statistical methodology was first used to identify the most discriminating hyperplane separating two groups of images (from healthy controls and patients with schizophrenia) contained in the input data. After this, the present work makes explicit the differences found by the multivariate statistical method by subtracting the discriminant models of controls and patients, weighted by the pooled variance between the two groups. A variational level-set technique was used to segment clusters of these differences. We obtained a label of each anatomical change using the Talairach atlas. We used a data set that contains images of 43 patients with schizophrenia and 25 healthy controls. All these images were acquired using a 1.5T Philips Gyroscan S15-ACS MRI scanner (Philips Medical Systems, Eindhoven, The Netherlands), including a series of contiguous 1.2 mm thick coronal images across the entire brain, using a T1-weighted fast field echo sequence (TE = 9 ms, TR = 30 ms, flip angle 30°, field of view = 240 mm, 256 x 256 matrix). All the images were reviewed by a MR neuroradiologist. Results: All the data was analysed simultaneously rather than assuming a priori regions of interest. As a consequence of this, by using active contour models, we were able to obtain regions of interest that were emergent from the data. The results obtained from these procedures were compared using as gold standard literature reviews of meta-analyses relating schizophrenia with neuroanatomical alterations. The results were evaluated according to their sensitivity and selectivity. Sensitivity measures the rate of ‘‘correct’’ answers provided by our framework, whereas selectivity measures how objective the framework is. We obtained around 0.28 of selectivity and 0.71 of sensitivity, meaning that 71% of the gold standard was covered by the results obtained and that 28% of the points generated by the procedures discussed in this paper were relevant with respect to the assumed gold standard. Discussion: We propose an integrated framework for classifying and interpreting patterns of schizophrenia from 3D MR images using a combination of statistical discriminant analysis and active contour models. We observed a statistical difference of 3D MR brain images of adults suffering from schizophrenia compared to a healthy control group. This investigation provides a suitable framework for characterising the high complexity of magnetic resonance images in schizophrenia as the results obtained indicate a high sensitivity rate with respect to the gold standard. Reference: Santos PE, Thomaz CE, dos Santos D, Freire R, Sato JR, Louzã M, et al. Exploring the knowledge contained in neuroimages: statistical discriminant analysis and automatic segmentation of the most significant changes. Artif Intell Med. 2010;49(2):105-15.

Longitudinal white mater changes in affective and non-affective psychosis

Renata R. C. Colombo1, Maristela S. Schaufelberger1, Luciana C. Santos1, Fábio L. S. Duran1, Paulo R. Menezes2, Marcia Scazufca2, Geraldo F. Busatto1, Marcus V. Zanetti1

1Departamento e Instituto de Psiquiatria, Faculdade de Medicina da Universidade de São Paulo, São Paulo, SP, Brasil/2Departamento de Medicina Preventiva, Faculdade de Medicina da Universidade de São Paulo, São Paulo, SP, Brasil

Background: The occurrence of white matter (WM) abnormalities in psychotic disorders has been suggested by several cross-sectional studies investigating brain pathology and neuroimaging measures. However, few studies have evaluated the existence of progressive WM changes associated with the course of illness using a longitudinal design, with conflicting results. We aim to assess WM volume changes in both schizophrenia and affective psychosis after a 1-year follow-up period after the first-episode using voxel-based morphometry. : One hundred and twenty-two individuals presenting with their first psychotic episode (62 fulfilling criteria for schizophrenia/schizophreniform disorder, 46 affective psychosis, and 14 other psychotic disorders), as well as 94 epidemiologically recruited controls underwent MRI scanning at baseline. After a mean follow-up period of approximately 14 months, 39 schizophrenia, 31 affective psychosis and 52 control individuals were re-scanned. T1-weighted images were processed with the Statistical Parametric Mapping (SPM2) package and the rates of WM change over time were investigated using a diagnostic group-by-time interaction approach, with the intervals between scans being included as a nuisance variable. Only resulting clusters comprising at least 20 voxels, and with p < 0.05 (Family-wise error corrected – FWE) were considered significant. Results: We failed to find any significant region of WM reduction or enlargement over time in the schizophrenia group relative to controls. However, the affective psychosis group showed a foci of volumetric decrease in the left medial frontal gyrus WM compared to the controls, which achieved a trend level of statistical significance (p-FEW = 0.089). Discussion:
The present results suggest that affective psychosis, but not schizophrenia, is associated with progressive WM abnormalities affecting the left frontal lobe.

Correlation of Schizophrenia Cognition Rating Scale (SCoRS) and the P300 in patients with schizophrenia

Keliane de Oliveira1, Rodrigo Ferretjans1, Rafael R. Santos1, Fernanda C. Guimarães1, Salvina M. de Campos1, Lívia A. Rodrigues1, Antonio L. Teixeira2, Eustaquio C. dos Santos1, João V. Salgado1,2


1Hospital de Ensino do Instituto Raul Soares/FHEMIG, Belo Horizonte, MG, Brasil/2Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brasil

Background: The P300 is an event-related potential that is altered in patients with schizophrenia. Presumably, the P300 is related to voluntary attention: individuals should signal a rare auditory stimulus, while ignoring the frequent stimuli. There is evidence that the patients have reduced amplitude of the wave that typically occurs 300 ms after the rare stimulus (P300). However, it is not clear how the changes detected in this test relate to the impact of cognitive dysfunction in the patients’ real life. The SCoRS is a 20-item structured interview that assesses how cognitive deficits affect the day-to-day functioning of patients. The correlation of P300 with SCoRS may clarify the implications of P300 performance on patients’ real life. : Two independent researchers assessed 20 stabilized patients with schizophrenia on the P300 and SCoRS, respectively. In its complete form, the SCoRS is rated by the patient, by an informant (usually a familiar) and by an interviewer. In the present study, only the SCoRS score given by the interviewer was considered. A Spearman correlation analysis was conducted by the program SPSS and multiple correlations were corrected by the Bonferroni method. Results: After correction for multiple correlation, the only significant correlation that remained was SCoRS question 11 (ability to concentrate for reading a book or newspaper), which correlated negatively with the P300 amplitude (r = -0.621, p = 0.002). Discussion: The P300 waveform amplitude relates specifically to the only SCoRS item that assesses the deficit in tasks that require attention. The specificity of this relationship points to the good capacity of SCoRS identifying attention deficits in these patients and their repercussions on their daily life.

Effects of minocycline on regional cerebral blood flow in schizophrenia

Cristiane R. de Marque1, Cristiano Chaves1, Lauro Wichert-Ana1, José Alexandre de S. Crippa1,2, Antônio W. Zuardi1,2, Glen B. Baker2,3, Francisco S. Guimarães1, Serdar M. Dursun2,3, Jaime E. C. Hallak1,2


1Universidade de São Paulo, Ribeirão Preto, SP, Brasil/2National Science and Technology Institute − Translational Medicine − CNPq, Ribeirão Preto, SP, Brasil/3University of Alberta, Edmonton, Alberta, Canada

Background: Minocycline is a broad spectrum tetracycline antibiotic with growing evidence of neuroprotective effects in neurological diseases and in schizophrenia. Three recent trials reported a broad symptomatic improvement when minocycline was added to usual antipsychotic treatment in schizophrenia (Levkovitz et al., 2008; Miyaoka et al., 2007; 2008). However, the effects of minocycline in the central nervous system remain obscure and have not been systematically studied using neuroimaging techniques. We report here the effects of minocycline on regional cerebral blood flow (rCBF) in patients with schizophrenia after twelve months of treatment with adjuvant minocycline or placebo. : A total of 24 patients with schizophrenia according to DSM-IV criteria, in their first five years of disease, and stable on medication four weeks prior to baseline, were studied. The experiment was approved by the local ethics committee. Patients were blinded to the medication they received and randomized to one of two groups (minocycline 200 mg/day or placebo). Brain SPECT scans were acquired 20 minutes after the injection of 99mTc-ECD, using a double-head SOPHATM DST gamma-camera, in a 128 x 128 matrix and 32 projections by head (75,000 counts/frame/head). Images were analyzed using Statistical Parametric Mapping software (SPM). Reconstructed transaxial datasets were converted to Analyze format and reoriented to neurological convention. Placebo images were realigned to minocycline images using sinc interpolation. Linear and nonlinear deformations were used to register images to the SPM SPECT template, which is based on the Montreal Neurological Institute template. Finally, an isotropic Gaussian filter of 12 mm was applied to diminish interindividual differences and to allow the subsequent application of parametric statistical tests. Results: Between-condition (minocycline vs. placebo) comparisons of regional tracer uptake were performed using paired t-tests. The regional ECD uptake of every voxel in each subject was standardized to the mean global uptake of the image in that subject, using proportional scaling. Only voxels with signal intensities above a threshold of 0.8 of the global mean entered the statistical analysis. The resulting statistics were transformed to Z-scores, thresholded at Z = 2.33 (corresponding to p < 0.01, one-tailed), and displayed as 3-D statistical parametric maps.
Minocycline augmentation of antipsychotic treatment significantly reduced positive and negative symptoms when compared to placebo. Significantly decreased ECD uptake in the minocycline relative to the placebo condition was evident in the right parahippocampal gyrus (Brodmann area - BA30), right frontal superior gyrus (BA11), right orbitofrontal gyrus (BA11), right frontal inferior gyrus (BA45), right temporal inferior gyrus (BA37), left orbitofrontal gyrus (BA47) and left temporal inferior gyrus (BA20). Discussion: Although the exact mechanism of minocycline’s neuroprotective action remains unclear, it may involve several different actions, including anti-inflammatory effects, anti-apoptotic properties and effects on signaling pathways. The improvement on positive and negative symptoms, simultaneously with reduced perfusion in the above mentioned brain areas, compared to placebo, may have been mediated by modulation of glutamatergic transmission after minocycline treatment. Minocycline was shown to be effective in improving symptoms in schizophrenic patients, and these effects seemed to be related to changes in perfusion in limbic regions directly affected in schizophrenia.

Late paraphrenia: fictional report in a Charles Dickens Novel (1849)

Isaac Charam1


1Universidade Federal Fluminense, Rio de Janeiro, RJ, Brasil


Background: Accurate descriptions of late paraphrenia may be found in fictional novels from various countries before its first descriptions by Kraepelin in the 8th revision of his treatise, and Guislain (1797-1860). We describe herein one of such accounts, found in a Charles Dickens novel published in England in 1849. : Evaluation, by a psychiatrist, of text extracts from the autobiographical novel by Charles Dickens, named "David Copperfield". Results: One of the key characters described in ''David Copperfield'' is an elderly individual called Mr. Dick. This gentleman used to keep a personal diary, and in this book he wrote that King Charles I (died by execution in 1649) often communicated with him and distracted his mind. Mr. Dick is also described by Dickens as often amused or entirely oblivious to the King's interferences in his mind. At other times, he wrote in his diary that the King used to come and disturb him. On the other hand, he used to participate intimately in his family life. Mr. Dick accepted to be David's tutor, along with his aunt, and he was always consulted when she had difficulties in making decisions. Discussion: The above account, which predates the descriptions by Kraepelin and Guislain, is compatible with the concept of ''Paraphrenia (late)'', a disorder characterised by the development of either a single delusion or a set of related delusions that are usually persistent and, sometimes, lifelong.

Psychotic symptoms in pediatric bipolar disorder are associated with impairment in executive functions

Cristiana C. Rocca1,2, Ana Kleinman2, Ana Gurgel1, Geraldo F. Busatto3, Beny Lafer2, Sheila C. Caetano2,3

1Unidades de Psicologia e Neuropsicologia da Universidade de São Paulo, São Paulo, SP, Brasil/2Programa de Assistência e Pesquisa em Transtorno Bipolar (PROMAN), Instituto de Psiquiatria, Faculdade de Medicina da Universidade de São Paulo, São Paulo, SP, Brasil/3Laboratório de Neuroimagem em Psiquiatria (LIM-21), Departamento de Psiquiatria, Faculdade de Medicina da Universidade de São Paulo, São Paulo, SP, Brasil

Background: Pediatric bipolar disorder (PBD) is a severe psychiatric illness, characterized by recurrent episodes of mania and depression, and significant functional impairment. Approximately 40% of the children and adolescents with PBD present psychotic symptoms. Psychotic symptoms have been associated with episode severity in different stages of the disease. Moreover, psychotic symptoms have a significant impact on cognition. Studies have shown that PBD subjects with psychotic symptoms present normal overall intelligence, but they have specific impairments in executive function, language and verbal memory. Executive function is characterized by a set of mental processes that helps the connection between past experience and present action. It refers to a person’s ability to manage and regulate a collection of basic cognitive and emotional processes. Executive functions are used to perform activities such as planning, organizing, strategizing, paying attention, remembering details, and managing time and space. A person lacking effective executive function skills tends to be less productive or successful in school and in everyday life activities. Our aim was to examine the influence of psychotic symptoms on children and adolescents with PBD by assessing two aspects of the executive functions: planning skills and mental flexibility. In order to do so, we compared subjects diagnosed with PBD with and without psychotic symptoms and healthy controls. We expected to find more impairment in the executive functions of the PBD patients with psychosis. : We compared 11 children with PBD and psychotic symptoms, 14 children with PBD without psychosis and 40 healthy controls. The following tests were used: The Rey-Osterrieth Complex Figure Test (ROCFT), the Tower of Hanoi test and the Wisconsin Card Sorting Test (WCST). Results: The PBD psychosis group did not present difficulties to copy the figure in the ROCFT, but they showed an impaired recall of the figure in comparison with the PBD without psychosis group and healthy controls (p = 0.032). The Tower of Hanoi test showed that the PBD with psychotic symptoms group presented higher number of movements to accomplish the task with three disks (p = 0.040) and spent more time to finalize the 5 attempts in the 4 disks step (p = 0.023), compared with the performance of the PBD without psychosis group and healthy controls. However, the three groups did not differ on the number of errors. There were no significant differences among the groups in the WCST in terms of perseverative errors and lost of set. Discussion: The PBD with psychotic symptoms group had more difficulties to remember the ROCFT and to find the solution in the Tower of Hanoi test. The PBD with psychotic symptoms group also needed a higher number of movements and more time to solve the most difficult task; although the accuracy was maintained. The Tower of Hanoi test assesses executive processes such as planning, working memory, inhibition and fluid intelligence. The presence of psychotic symptoms in children and adolescents with PBD interferes with planning skills and suggests difficulties with fluid intelligence.

Pseudocyesis and schizophrenia
Roberto B. R. Taveira1, Leonardo F. Caixeta1, Daniela L. R. Taveira2, Alexandre A. C. Peleja1, Norami M. Barros1, João Henrique V. Pedroso1

1Universidade Federal de Goiás, Goiânia, GO, Brasil/2Pontifícia Universidade Católica de Goiás, Goiânia, GO, Brasil

Background: Pseudocyesis is considered a rare condition. Due to psychological or somatic manifestations, or even both, a non-pregnant patient believes to bear a child. Usually, there is a misinterpretation of body changes associated with emotional aspect of pregnancy or thought disorders (or chronic mental disorders), what makes pseudopregnancy a complex disorder to deal with, starting with its classification; the DSM IV-TR ranks it as a "Somatoform Disorder Not Otherwise Specified" resulting in underdiagnoses and misdiagnoses. : This study involves a review of the literature on studies indexed in PubMed between 1937 and September of 2010 using the keywords "PSEUDOCYESIS" or "pseudopregnancy" or "delusion of pregnancy" or "phantom pregnancy". Also, comparing it to a collected data of twenty (20) patients who were diagnosed with pseudocyesis over a ten-year period in Goiania catchment area (Brazilian central region), with focus on their psychopathological presentation and related psychiatric diagnosis based on DSM-IV criteria. Results: The mean age of this pseudocyesis sample was 35 years and the disorder was found more commonly among women, although two men also presented it. There is a large variation in pseudocyesis symptomatological presentation, with and without physical pregnancy modifications; with and without psychotic symptoms, but the most common somatic manifestations are: abdominal enlargement, breast changes, menstrual irregularities, fetal movements' feelings, galactorrhea and gastrointestinal symptoms. The diagnoses more associated with pseudocyesis were bipolar disorder (8 cases) and schizophrenia (6 cases). Serum plasma exams confirmed the absence of pregnancies in all cases. Management included psychotherapy associated with psychopharmacological use in most of cases. Discussion: There is no research showing the incidence of pseudocyesis in Brazil, so our data base was compared with the literature of other countries. In this process, we found many similarities, including age, socioeconomic status, symptoms, underlying disorders and history of strong emotions concerning pregnancy or great desire to obtain more attention. The main psychiatric syndromes observed described in the literature concomitant with pseudocyesis are schizophrenia, bipolar disorder (depressive and manic phases), organic psychosis, anxious disorder, mood disorders with psychosis, conversion neurosis, psychosis, dementias and major depression. There are two main reasons why pseudocyesis is commonly associated with schizophrenia. First because of the delusions, which are common in schizophrenia; second because of the misinterpretation of somatic symptoms caused by first-generation antipsychotics used to treat those patients. The main pseudocyesis signs in schizophrenic patients are illusions, hallucinations (of fetal movements, for example) and personality alterations, and there is a higher hostility level in schizophrenic women presenting pregnancy delusion if compared to the matched controls ones. Pseudocyesis can occur in men, despite rare, and researches show that there is always an underlying psychosis, and often a sexuality conflict. In this work found two male patients, both with hebephrenic schizophrenia and conflict about their sexuality. There is not a standard treatment for pseudocyesis because there are many mechanisms that can lead to the disorder. A psychiatric intervention is often required, as the resolution of pseudocyesis can come with strong emotional reactions, as well as depressive manifestations and suicidal attempts. This is the main reason why pseudocyesis should be more studied and known by all doctors. 

Guidelines for assessment of the clinical relevance of anomalous/psychotic experiences

Alexander Moreira-Almeida1

1Núcleo de Pesquisa em Espiritualidade e Saúde, Faculdade de Medicina da Universidade Federal de Juiz de Fora, Juiz de Fora, MG, Brasil

Background: There is an increasing literature showing a high prevalence of psychotic and dissociative symptoms in the general population. However, most of our knowledge of those experiences is based on clinical, often hospitalized, samples. Spiritual experiences can be confused with psychotic and dissociative symptoms, being frequently a challenge for the differential diagnosis. Some anomalous/spiritual experiences may be confused with psychotic episodes since they might involve experiences of external influences on thought and behavior, beliefs of delusional characteristics and hallucinations, classic symptoms of schizophrenia. On the other hand, psychotic patients frequently present a symptomatology of religious/spiritual content. Based on the considerations above, it would useful better explore guidelines for assessment of the clinical relevance of anomalous/psychotic experiences. : We searched electronic databases (PubMed, PsycINFO, Scopus, and SciELO) using relevant keywords for articles with original psychiatric and psychological data on anomalous/spiritual experiences, and psychotic experiences in non-clinical populations. We also analyzed the references of the articles found and contacted authors for additional references and data. Results: There is strong evidence that psychotic and anomalous experiences are widespread in the population and that most of them are not related to psychotic disorders. However, in population surveys, reports of psychotic symptoms have been related to higher emotional distress and disability. On the other hand, about 1/3 of those reporting psychotic experiences had no psychiatric disorders as assessed with a structured clinical interview. Frequently, spiritual experiences involve non-pathological dissociative and psychotic experiences that are often related to indicators of good mental health. Although spiritual experiences are not usually related to mental disorders, they may cause transient distress and are often reported by psychotic patients. Discussion: In the last decade, it has become clear that psychotic experiences are highly prevalent in the general population, and that in around 90% of the cases they are not associated with psychotic disorders. Calling these experiences “psychotic symptoms” would produce about 90% of false positives. Epidemiological data suggest that people having psychotic experiences form a heterogeneous group in which some suffer from health disorders but not others, as suggested by studies on psychotic experiences in relation to spiritual experiences. Recognition by clinicians and the general population that psychotic experiences are very prevalent and not necessarily pathological may not only improve clinical practice, but also contribute to decrease the stigma associated with psychotic disorders, based on the wrong assumption that they are something completely different from common human experience. We propose some features that suggest the non-pathological nature of an anomalous/psychotic experience: lack of suffering, lack of social or functional impairment, compatibility with the patient’s cultural background and recognition by others, absence of psychiatric comorbidities, control over the experience, and personal growth over time.

Effects of cannabidiol and rimonabant on contextual fear conditioning in a new animal model of schizophrenia

Raquel Levin1,2, Valéria Almeida1,2, Fernanda F. Perez1,2, Mariana B. Calzavara2, Suzy T. Niigaki1,2, Mayra A. Suiama1,2, Antonio W. Zuardi3, Jaime E. Hallak3, José A. Crippa3, Vanessa C. Abílio1,2

1Departamento de Farmacologia, Universidade Federal de São Paulo, São Paulo, SP, Brasil/2Laboratório Interdisciplinar de Neurociências Clínicas, Universidade Federal de São Paulo, São Paulo, SP, Brasil/3Departamento de Neurociência e Ciência do Comportamento, Universidade de São Paulo, Ribeirão Preto, SP, Brasil

Background: Clinical and neurobiological findings suggest that cannabinoids and their receptors are implicated in schizophrenia. Cannabidiol, a non-psychotomimetic compound of the Cannabis sativa, has been reported to have central therapeutic actions, such as antipsychotic and anxiolytic effects. We have recently reported that spontaneously hypertensive rats (SHR) present a deficit in contextual fear conditioning (CFC) that is specifically ameliorated by antipsychotics and aggravated by proschizophrenia manipulations. These results led us to suggest that the CFC deficit presented by SHR could be used as a model to study emotional processing impairment in schizophrenia. On the other hand, anxiolytic compounds are able to decrease CFC in control animals. The aim of this study is to evaluate the effects of cannabidiol and rimonabant (CB1 receptor antagonist) on contextual fear conditioning in SHR and wistar rats. : Male adult Wistar rats (WR) and SHR (7-10/strain/drug) were treated with vehicle, 1, 5 or 15 mg/kg cannabidiol (experiment 1) or vehicle, 0.75, 1.5 or 3 mg/kg rimonabant (experiment 2). Thirty minutes later, the animals were submitted to the acquisition session of the CFC in which 0.4 mA footshocks were presented in association with a context. During the test session performed 24h later, the freezing duration (a fear response) was quantified without the presentation of the footshocks. Results: In experiment 1, vehicle-treated SHR showed a decreased freezing response when compared to WR that was attenuated by 1 mg/kg cannabidiol. Moreover, all cannabidiol-treated WR presented a decreased freezing response when compared to control rats. In experiment 2, vehicle-treated SHR showed a decreased freezing response when compared to WR that was attenuated by 3 mg/kg rimonabant. Discussion: Our results suggest a therapeutical potential of cannabidiol and rimonabant to treat the emotional processing impairment presented in schizophrenia. In addition, our results reinforce the anxiolytic profile of cannabidiol.

Association between stages of change and schizophrenia in cannabis dependent treatment-seeking patients

Hercilio Oliveira1, Andre Malmergier1

1Universidade de São Paulo, São Paulo, SP, Brasil

Background: Motivation is a key factor associated with illicit drug dependence treatment seeking. The transtheoretical model has been used in many fields and it can be considered a valid construct to describe how people may change their addictive behaviors. There are few data on the association of cannabis dependence and motivation for treatment in cannabis dependent treatment-seeking patients and the majority of the studies that have assessed motivation for treatment in cannabis users excluded patients with comorbid psychiatric disorders. The assessment of motivation in cannabis-dependent patients with comorbid disorders, such as schizophrenia, could shed light on the complex variables associated with psychotic disorders, drug addiction and treatment seeking. This study aims to assess comorbid disorders and motivation for change in treatment-seeking cannabis dependent patients at a specialized outpatient. : Subjects -" This study assessed 80 patients who sought treatment for cannabis related problems at a specialized outpatient clinic in the Psychiatric Institute of the Medical School of the University of Sao Paulo, Brazil, in the period of 2007-2010. Instruments -" 1) SCAN-PSE10; 2) URICA; 3) ASI. Statistical Analysis -" The association between demographics, ASI scores, and concurrent disorders was performed through a logistic regression. The ANOVA was used to compare patterns of drug use and stages of change. The associations among categorical variables were performed through Chi-square tests and the Fisher's Exact Test. A significance level of 0.05 was considered. Results: Demographic Data -" Mean age was 30.1 years old (SD = 9.4). Participants were predominantly male (81.2%), single (66.2%), employed (62.5%), and had more than 8 years of education (87.5%). Among the 80 participants, 61.2% (n = 49) met criteria for concurrent disorders. The most frequent concurrent disorder was major depression (22.4%). Three patients (3.8%) met criteria for bipolar disorder. Seven patients (8.8%) met the criteria for panic disorder; nine subjects (11.2%) met the criteria for generalized anxiety disorder and two participants for obsessive-compulsive disorder (2.5%). Seven subjects (8.8%) met the criteria for schizophrenia. Stages of Change and Concurrent Psychiatric Disorders -" Participants with depressive disorder scored higher in the contemplation stage of change (35.2%) and participants with schizophrenia scored higher in the precontemplation and the contemplation stages of change. After performing the Fisher and Chi-square non parametric tests, the participants with schizophrenia had significant higher scores on precontemplation and contemplation stages (p = 0.031) when compared to not schizophrenic patients. Discussion: This study highlighted the complex relationship between cannabis dependence and concurrent disorders in treatment-seeking patients. This relationship can have an impact on critical variables such as motivation for treatment. The high prevalence of concurrent psychiatric disorders in cannabis dependent individuals coming for treatment should serve as a stimulus for early screening and treatment of those concurrent disorders. Professionals involved in healthcare should be aware of the magnitude of this association and should be prepared to provide specific treatment plans, including specific facilities for cannabis dependent patients with severe concurrent psychiatric disorders.


Recovery in patients with schizophrenia: a study of reliability and validity of recovery assessment scale (RAS)

Tiago Ribeiro Silva1, Rodrigo Affonseca Bressan1, Cecília Cruz Villares1

1Universidade Federal São Paulo, São Paulo, SP, Brasil


Background: The concept of recovery in mental health has been understudied in Brazil, but it's already a model and a movement of great importance in countries like USA and in Europe, studied primarily with schizophrenic patients. This concept, which is still without a translation that represent its significance for the Portuguese, can be understood by how the patient reacts to his illness, developing a learning process and a new attitude and vision of himself. To help understand this concept, words like overcoming and life expectation may be associated with this concept. Researchers and patients have created and driven devices and instruments that guide professionals and mental health services to assist their patients toward recovery. Among the tools of recovery, there is the Recovery Assessment Scale (RAS), a scale developed and validated by analysis of four patients stories, administered to 35 patients at the University of Chicago, in partial hospitalization program. This scale has 41 items, focusing on four categories: self-esteem, empowerment, social support and quality of life, and it had Cronbach's Alpha = 93. Currently in Brazil, there is no recovery instrument translated and validated into Portuguese yet. This paper presents the preliminary results of a master's project focused on the reliability and validity of the instrument RAS. This project includes a study of PROESQ -" Schizophrenia Clinic of Unifesp (Federal University of São Paulo), in which all subjects underwent a psychiatric interview, neuropsychological and clinical tests (blood, DNA, and neuroimaging). : The application of the instrument was performed in 104 patients followed up or not in weekly PROESQ’s groups that agreed to participate and signed a consent form. The RAS was translated and back translated, receiving a semantic and cultural adaptation to Portuguese. To validate this instrument three others instruments that correlate with the measurements assessed by scale were administered: WHOQOL-bref (scale of quality of life); Inventory Independent Living Skills (ILSS-SR) and the Self-Assessment Questionnaire of Occupational Functioning -" SAOF. Besides these instruments will be included in the analysis some data as a measure of the scale of the Positive and Negative Syndrome-PANSS. Results: The project is being analyzed and the data will be analyzed using the statistical program SPSS version 17.0. It is expected that the RAS will be validated and demonstrate itself reliable for measuring the process of recovery of patients with schizophrenia in the Brazilian context. Also it is expected to verify a positive association between RAS's items with factors such as occupational performance and social functioning, quality of life, self-esteem and intensity of symptoms. Discussion: From the validation of the RAS in the Brazilian context, strategies can be developed with professionals, to insert it to the daily work of mental health services because it is a useful, unique and easy to use instrument, capable to develop practices that help patients in their recovery process.

Time to rehospitalization in patients with schizophrenia discharged on first generation antipsychotics, non-clozapine second generation antipsychotics, or clozapine

Ana Paula Werneck1, Jaime Cecilio Hallak2, Eduardo Nakano3, Helio Elkis1
1Universidade de São Paulo, São Paulo, SP, Brasil/2Universidade de São Paulo, Ribeirão Preto, SP, Brasil/3Universidade de Brasília, Brasília, DF, Brasil
Background: Rehospitalization is an important outcome of drug effectiveness in schizophrenia (1). In this study, the hypothesis that clozapine and some second generation antipsychotics (SGA) were superior to first generation antipsychotics (FGA) in preventing rehospitalization of patients with schizophrenia discharged from a university hospital in Brazil was tested (2). : A retrospective observational study was conducted designed to evaluate time to rehospitalization of patients with schizophrenia discharged on a regimen of oral FGA, depot FGA, risperidone, olanzapine and amisulpride, other SGA, or clozapine, during a three-year follow-up period. Survival curves were estimated using the product limit (Kaplan-Meyer) method. The significance of difference among groups was measured by the Mantel-Cox- log-rank test. The Cox proportional hazard regression models were used to analyze covariates such as demographics, number of previous hospitalizations, and number of previous antipsychotics and length of hospitalization. Results: Of 464 patients with schizophrenia discharged from hospital, 242 met criteria for study entry. Higher rehospitalization rates were observed in patients treated with depot FGA (30%), risperidone (30%) and other SGA groups (28.5%), respectively. After Bonferroni correction clozapine was significantly associated with lower rehospitalization risk compared with risperidone (Mantel- Cox chi square = 9.49, p = 0.0021) and a trend toward significance between clozapine and FGA (Mantel- Cox chi square = 6.43, p = 0.0112). The risk of rehospitalization in patients on olanzapine and amisulpride, and oral FGA, was similar to that of patients in use of clozapine. Patients who used amisulpride or olanzapine (11%), oral FGA (12%) or clozapine (15%) had the lowest hospitalization rates while those taking depot (30%), risperidone (30%) or other SGA (28%) had the highest hospitalization rates. Discussion: In terms of prevention of rehospitalization clozapine was more effective than risperidone and SGA had similar rates of rehospitalization than FGA. However these results are limited by the heterogeneity of illness severity across the groups.

Architectural factors in the etiology of schizophrenia
Jan A. Golembiewski1
1Clinical Critical Research Group, Faculty of Architecture, Planning and Design, University of Sydney, Sydney, NSW, Australia
Background: The question of architecture in the etiology and treatment of schizophrenia has had a long but patchy history, with few authors able to find sufficient evidence to compellingly match architectural effects to the syndrome. Yet the architectural and urban environment is the main buffer that most people have against any unwanted and stressful ecological influences. A person's home is not only there to protect from the weather, but also against negative social interactions and downward social mobility. But for some reason, the shielding value of the architectural milieu breaks down in schizophrenia, and at times it may even make the condition worse.
: This meta-analysis looks at the ecological dynamics of schizophrenia to draw novel conclusions that are supportable with robust evidence. Results: 1. Architectural and urban environments mediate the ecological effects of urbanicity, society, civic services, poverty, atmosphere, geography and identity. Available data demonstrates how these factors are multiplied by the architectural and urban milieu, to turn small risk factors into large ones. 2. Under normal conditions, the architectural milieu provides passive protection. This enables autonomy and breeds the sensibilities associated with normality: comfort, happiness and a sense of self. As schizophrenia develops, the influence of the immediate environment becomes increasingly active, triggering hallucinations and delusions, and destroying any sense of comfort, to the point where camping outside in the rain is often preferable to being indoors. Evidence is found to support a hypothesis to explain this bizarre phenomenon. 3. Quality of the living environment is a good indicator of degree of mental illness. 4. Improvements in architectural environment and recovery from illness are found to broadly correlate. Discussion: The main case for implicating the physical environment in the etiology of schizophrenia relates to well observed reductions in frontal brain function. When frontal function is normal, the environment suggests behavior. When the frontal lobe has been lesioned, the environment determines behavior; this effect is known as "utilization behavior syndrome" and "environmental dependency syndrome". Schizophrenia occupies a difficult middle-ground, where the environment demands behavior, as if it were animate. This potentially causes the characteristic hallucinations and delusions of schizophrenia, but further, it may make the architectural milieu appear hostile.



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Órgão Oficial do Departamento e Instituto de Psiquiatria
Faculdade de Medicina - Universidade de São Paulo