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-Valencia1,
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-Souza1,2,3,
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 Sousa1,
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. Moreira1,
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. Sa1,
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’Souza1,2,3,
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. Ricardo1,2,
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. Rosa1,
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. criteria2
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 _/img/u.gif) 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, Brasil
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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