RAFAEL AUGUSTO TEIXEIRA DE SOUSA
Projetos de Pesquisa
Unidades Organizacionais
LIM/27 - Laboratório de Neurociências, Hospital das Clínicas, Faculdade de Medicina
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conferenceObject Increased GDNF but not BDNF Plasma Levels in Type II Compared to Type I Bipolar Disorder(2013) ZANETTI, Marcus V.; TEIXEIRA, Antonio L.; CHAIM, Tiffany M.; SOUSA, Rafael T. de; TALIB, Leda L.; GATTAZ, Wagner F.; BUSATTO, Geraldo F.; MACHADO-VIEIRA, RodrigoBackground: The brain-derived neurotrophic factor (BDNF) is a neurotrophin important for synaptic plasticity and neurogenesis, whereas the glial cell-line derived neurotrophic factor (GDNF) modulates the activity of monoaminergic neurons and glial cells. Previous works have suggested that abnormal peripheral levels of these proteins might relate to different mood states in bipolar disorder (BD), but none study so far have evaluated it with regard to potential differences between the types I (BD-I) and II (BD-II) subtypes of the disorder. Methods: Eighteen BD-I and 19 BD-II patients presenting with an acute mood episode (depressive, manic or mixed), and 23 healthy controls were studied. Plasma levels of BDNF and GDNF were measured using enzyme-linked immunosorbent assay (ELISA). Results: BD-II individuals showed significantly increased levels of GDNF compared to both BD-I patients and controls (ANOVA, df=2, F= 5.74, p=0.005; Tukey for post hoc comparisons). When we focused our analysis on the treatment-naïve patients only (14 BD-I and 13 BD-II), this result became even more significant (ANOVA, df=2, F= 7.33, p=0.002). No significant between-groups differences were observed on BDNF levels. Also, no significant correlation was observed between BDNF or GDNF levels and depressive and manic symptoms. Conclusions: BD-II at an acute phase of the illness is associated with increased plasma levels of GDNF. Previous use of mood stabilizer and antipsychotic agents might produce a chronic effect on GDNF production.conferenceObject Lithium Monotherapy Increases Nitric Oxide Levels During Depressive Episodes in Bipolar Disorder(2013) SOUSA, Rafael T. de; ZANETTI, Marcus V.; MOURO, Margaret G.; HIGA, Elisa M. S.; GATTAZ, Wagner F.; MACHADO-VIEIRA, RodrigoBackground: Nitric Oxide (NO) is precursor of peroxynitrite, a molecule which causes oxidative stress. Several studies have associated bipolar disorder (BD) with altered NO and oxidative stress. Besides that, evidences suggest a dual role of NO in depression, since both increase or decrease in NO levels have been associated with antidepressant efficacy in preclinical models. The present study evaluates NO in subjects with bipolar depression before and after a 6-week lithium treatment. Also, NO in patients and controls was compared. Methods: Patients with BD in a depressive episode (n=22) were treated with lithium monotherapy for 6 weeks. Blood samples were collected at baseline and after 6-week lithium treatment, also compared to healthy controls (n=28). NO in patients at baseline and at endpoint and in healthy controls was measured with chemiluminescence method. Results: Patients in a depressive episode had an increase in NO levels from baseline to endpoint (Wilcoxon Signed Ranks Test, z=-2.11, p=0.035). NO levels showed no difference in patients compared to healthy controls. Conclusions: This is the first study evaluating lithium effects on NO levels. Increased NO after lithium treatment suggests a potential role of NO pathways in the therapeutics of mood disorders.conferenceObject Increased Lactate Levels During Depressive Episodes and Reversal Effects by Lithium Monotherapy in Subjects with Bipolar Disorder(2013) MACHADO-VIEIRA, Rodrigo; ZANETTI, Marcus V.; OTADUY, Maria C. G.; SOUSA, Rafael T. de; COSTA, Alana C.; CHAIM, Tiffany M.; LEITE, Claudia C.; BUSATTO, Geraldo F.; GATTAZ, Wagner F.Background: Altered energy metabolism has been widely described in Bipolar Disorder (BD). However, brain lactate levels have been only evaluated in few studies with heterogeneous samples using magnetic resonance spectroscopy (MRS). These findings support the presence of dysfunctional brain energy production as a central component in the pathophysiology of BD. However, no study to date has evaluated brain lactate levels specifically in bipolar depression or even the effects of lithium treatment in brain lactate levels in subjects with BD. Methods: Twenty-four BD individuals (up to 5 years of illness duration) presenting with an acute depressive episode underwent MRS at baseline and after 6 weeks of lithium therapy at therapeutic doses. Lactate levels were measures in the cingulated cortex (CC). Clinical assessment was performed weekly using the 21-item Hamilton Depression Rating Scale (HDRS) and the Young Mania Rating Scale (YMRS). A group of age and gender-matched healthy controls (n=18) was also studied. Results: BD patients exhibited increased brain lactate in the CC relative to healthy controls at baseline. A significant decrease in brain lactate levels was observed after 6 weeks of lithium treatment, and correlated with clinical response (reduction ≥ 50% in HDRS scores). Conclusions: Lithium treatment produces a significant decrease in brain lactate levels of acutely depressed BD patients. This suggests that the clinical efficacy of lithium is also associated with reduction in the shift from aerobic to anaerobic metabolism observed in BD.- Formal Thought Disorder and language impairment in schizophrenia(2013) RADANOVIC, Marcia; SOUSA, Rafael T. de; VALIENGO, Leandro L.; GATTAZ, Wagner Farid; FORLENZA, Orestes VicenteSchizophrenia is a psychiatric illness in which disorders of thought content are a prominent feature. The disruption of normal flow of thought, or ""Formal Thought Disorder"" (FTD), has been traditionally assessed through the content and form of patients' speech, and speech abnormalities in schizophrenia were considered as a by-product of the disruption in conceptual structures and associative processes related to psychosis. This view has been changed due to increasing evidence that language per se is impaired in schizophrenia, especially its semantic, discursive, and pragmatic aspects. Schizophrenia is currently considered by some authors as a ""language related human specific disease"" or ""logopathy"", and the neuroanatomical and genetic correlates of the language impairment in these patients are under investigation. Such efforts may lead to a better understanding about the pathophysiology of this devastating mental disease. We present some current concepts related to FTD as opposed to primary neurolinguistic abnormalities in schizophrenia.
conferenceObject Lithium Increases Mitochondrial Complex I Activity in Bipolar Disorder(2013) SOUSA, Rafael T. de; ZANETTI, Marcus V.; FERREIRA, Gabriela K.; GATTAZ, Wagner F.; MACHADO-VIEIRA, Rodrigo; STRECK, Emlio L.Background: Evidences have directly involved a role for mitochondrial dysfunction and altered oxidative stress parameters in the pathophysiology of Bipolar Disorder (BD). In BD post-mortem brains, oxidative damage, impaired mitochondrial complex I activity and decreased expression of genes encoding mitochondrial complexes subunits, especially complex I, have been shown. Lithium treatment in BD showed to reverse some pathological changes and was associated with increased expression of gene encoding complex I subunit in post-mortem brain tissue. However, to our knowledge, lithium effects in mitochondrial complexes I-IV was not evaluated in clinical studies. Methods: Patients with BD in depressive episode (n=22) were treated with lithium for 6 weeks. Benzodiazepine or zolpidem use as needed to induce sleep was allowed and 3 patients had also other drugs associated with lithium. Age-matched healthy controls (n=23) were recruited for comparisons. Complex I-IV activities in leukocytes were evaluated before and after lithium treatment in BD subjects and healthy controls. Activities of complexes were measured spectrophotometrically. Results: Complex I activity increased from baseline to endpoint (Wilcoxon Signed Ranks Test, z=-2.0, p=0.046). Complexes II-IV activities at baseline and endpoint were not significantly different. Also, complexes I-IV activities did not differ between patients with BD and healthy controls. Conclusions: Lithium therapeutic and antioxidant effect in BD may be involved with increase in complex I activityconferenceObject Epistasis Between COMT Val(158)Met and DRD3 SER(9)Gly Polymorphisms on Cognitive Function of Individuals with Schizophrenia(2013) LOCH, Alexandre A.; BILT, Martinus T. van de; BIO, Danielle S.; PRADO, Carolina M. do; SOUSA, Rafael T. de; VALIENGO, Leandro L.; MORENO, Ricardo A.; ZANETTI, Marcus V.; GATTAZ, Wagner F.Background: The present study aimed to determine the influence of cathecol-O-methyl-transferase(COMT) Val158Met and dopamine receptor D3 (DRD3) Ser9Gly polymorphisms on cognitive functioning of individuals with schizophrenia and controls. Methods: Fifty-eight outpatients with schizophrenia from the Institute of Psychiatry, Sao Paulo, and 89 controls from the same geographical area with no psychiatric or neurological disorders were recruited. Neurocognitive battery assessed: attention, verbal memory, visual memory, visuospatial function, language, psychomotor speed, executive function, intelligence. DNA was extracted from peripheral blood and genotyped for COMT Val158Met and DRD3 Ser9Gly; real-time PCR allelic discrimination with TaqMan®SNP Genotyping Assays was used. Analyses of variance (ANOVAs) controlling for sex, age and years of education were used to compare neuropsychological performance between both genotypes in controls and in patients. Results: Worst executive function was observed for DRD3 Ser/Gly carriers in controls (r=0.07,p=0.04); no DRD3 genotype effect was seen in patients. Regarding COMT, Val/Val patients had significantly worse attention (r=0.12,p=0.02); for Met/Met both patients (r=0.15,p=0.02) and controls (r=0.10,p=0.01) showed worse executive functioning. For the interaction of COMT and DRD3 polymorphisms, genotypes had significant effect among executive function in controls and patients (ES=0.137,p=0.006); all controls had similar scores. COMT Val/Val patients also performed equally to controls. As COMT Met allele frequency increased, cognitive functioning worsened in patients; this effect was maximum when combined with DRD3 Ser/Ser. Conclusions: Results support the influence of combined genetic polymorphisms related to dopamine in cognitive functioning in schizophrenia. More studies considering epistatic effects of multiple polymorphisms should be conducted to assess candidate endophenotypes.conferenceObject Mitochondrial DNA Content in Bipolar Disorder(2013) SOUSA, Rafael T. de; ZANETTI, Marcus V.; UNO, Miyuki; GATTAZ, Wagner F.; MARIE, Suely K. N.; MACHADO-VIEIRA, RodrigoBackground: Consistent evidences support the role for mitochondrial dysfunction in Bipolar Disorder (BD) pathophysiology. Also, BD is associated with clinical and neuropsychiatric conditions which show any mitochondrial compromise, such as type 2 diabetes mellitus and Alzheimer’s disease, illnesses that showed altered mitochondrial DNA (mtDNA) content. Mitochondrial DNA (mtDNA) content has been proposed as a biomarker in several clinical conditions. The present study evaluates mtDNA content in patients with bipolar depression, comparing to healthy controls. Methods: BD patients in a depressive episode (n=23) (≥18 in the 21-item Hamilton Depression Scale) and no more than 5 years of mood disorder diagnosis entered the study. Patients were drug free for at least 4 weeks before inclusion. mtDNA copy number in patients was compared with healthy controls (n=24). Correlation between depressive symptoms and mtDNA copy number was calculated. mtDNA copy number (per cell) in leukocytes of patients and controls was determined by real time-PCR. Results: mtDNA copy number showed no significant difference between patients and controls (ANCOVA, F=0.56; df=1, 47; p=0.46). Also, no significant correlation was found between depressive symptoms and mtDNA content (Spearman, r=0.28, p=0.19). Conclusions: To the best of our knowledge, this is the first study evaluating mtDNA content in BD. The results suggest that mtDNA is not altered in depressive episodes of recent-onset BDconferenceObject Oxidative Stress Parameters in Recent-Onset Bipolar Disorder and Possible Lithium Antioxidant Effect(2013) SOUSA, Rafael T. de; ZANETTI, Marcus V.; TALIB, Leda L.; GATTAZ, Wagner F.; MACHADO-VIEIRA, RodrigoBackground: Several studies have shown oxidative stress (OxS) and imbalance of antioxidant enzymes in bipolar disorder (BD). Lithium is a gold-standard treatment in BD and showed a role in decreasing OxS. Despite few data available for recent-onset BD, increased antioxidant defenses were found in first episode of bipolar mania. No study, however, evaluated OxS parameters in depression of recent-onset BD and the effects of lithium treatment in OxS in bipolar depression. Methods: BD subjects in a depressive episode (n=25) with no more than 5 years of illness duration were enrolled and treated for 6 weeks with lithium monotherapy, although hypnotics use as needed was allowed. Blood samples were collected at baseline and after 6-week lithium treatment. Healthy controls (n=28) were used for comparison with patients. Tiobarbituric acid reactive substances (TBARS), superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx) activities were measured spectrophotometrically. Results: BD patients had increased CAT (ANCOVA, df=1, 47, F=56.60, p<0.001), enhanced GPx (ANCOVA, df=1, 49, F=12.20, p=0.001) and decreased SOD/CAT ratio (ANCOVA, df=1, 44, F=30.66, p<0.001) compared to healthy controls. Also, no differences in SOD or TBARS between subjects with BD and healthy controls was observed. Regarding lithium treatment effects, BD patients had a decrease in TBARS (Wilcoxon Signed Ranks Test, z=-2.81, p=0.005) levels, with no changes in other parameters. Conclusions: Results suggest that recent-onset BD may have enhanced antioxidant enzymes. Lithium showed efficacy against OxS, confirming its neuroprotective role.