RAFAEL AUGUSTO TEIXEIRA DE SOUSA
Projetos de Pesquisa
Unidades Organizacionais
LIM/27 - Laboratório de Neurociências, Hospital das Clínicas, Faculdade de Medicina
12 resultados
Resultados de Busca
Agora exibindo 1 - 10 de 12
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 Clinical Use of Genetic Polymorphisms as Markers of Refractoriness in Schizophrenia(2012) BILL, Martinus T. van de; PRADO, Carolina M.; OJOPI, Elida P. B.; LOCH, Alexandre A.; ZANETTI, Marcus V.; SOUSA, Rafael A. T.; MACHADO-VIEIRA, Rodrigo; GATTAZ, Wagner F.Background: Pharmacogenetics studies have demonstrated the importance of various neurotransmitter systems in mediating drug effectiveness. Due to the importance of the dopaminergic system in the activity of antipsychotics, proteins that regulate the availability of dopamine may influence the response to drug treatment, as the enzyme catechol-O-methyl-transferase (COMT), which catalyzes the breakdown of dopamine. Some associations have already been described between Val108/158Met polymorphism and response, with individuals carrying the Met allele presenting the best answer. However, most of the findings reported have not been universally replicated. Methods: The study enrolled 89 schizophrenia patients divided in two groups: 59 refractory patients according to IPAP algorithm (International Psychopharmacology Algorithm Project) and 30 non-refractory patients. Polymorphisms in COMT (rs4680), HTR2A (T102C, rs6314, rs1928042), HTR2C (rs6318, rs3813929), CHRNA7(rs7164043), BDNF (rs6265), DRD3 (rs6280) and GRM8 (rs7778604) genes were evaluated by allelic discrimination using the TaqMan® system. Results: regarding the polymorphism rs4680 (Val158Met) of the COMT gene, among the non-refractory patients we found 7% AA, 50% AG and 43% GG genotypes. Among refractory patients we found 20% AA, 59% AG and 21% GG. After the X2 test, we found a difference in the genotype distribution between the two groups (p=0.043). For the other polymorphisms in genes HTR2A, HTR2C, CHRNA7, BDNF, DRD3, and GRM8, no significant difference was found. Conclusions: Our findings do not confirm previous data. In our study there is a higher prevalence of individuals homozygous for Met in the refractory group and a higher prevalence of individuals homozygous for Val the non-refractory (p=0.043).conferenceObject A Longitudinal Study on the Neurobiological Basis of Antidepressant Efficacy in Bipolar II Disorder(2012) MACHADO-VIEIRA, Rodrigo; ZANETTI, Marcus V.; OTADUY, Maria C.; SOUSA, Rafael T. De; LEITE, Claudia C.; BUSATTO, Geraldo F.; GATTAZ, Wagner F.Background: Bipolar II disorder is a chronic and disabling psychiatric disorder, with subjects spending up to half of their time depressed. Current guidelines recommend the proof of concept agent lithium as a valuable treatment for acute bipolar II depression. However, little is known about the neurobiological basis of the antidepressant efficacy in bipolar II disorder. Methods: Fourteen drug-free individuals with a DSM-IV diagnosis of bipolar II disorder (BD-II) during a depressive episode (HAM-D≥18) were followed-up in a 6-week open-label trial with lithium monotherapy. All subjects had less than three lifetime mood episodes. 1H-MRS was performed at baseline and after 6 weeks (with additional 7Li-MRS at endpoint) Results: Lithium monotherapy showed a significant antidepressant efficacy in bipolar II depression. Post-treatment with lithium induced a significant increase in glutamate levels in the anterior cingulate cortex (ACC) compared to baseline levels, which was associated with brain lithium levels and clinical improvement of depressive symptoms. Conclusions: Our findings support a key role for ACC glutamate levels in the pathophysiology and therapeutics of Bipolar II disorder. These findings have important clinical and theoretical implications, also suggesting a potential role for glutamate as a valuable therapeutic target in Bipolar II depression. Keyword(s): bipolar disorder, depression, lithium, imaging, biomarkerconferenceObject 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.- Soluble Tumor Necrosis Factor Receptor 1 and 2 in Bipolar Depression and the Association with Lithium Treatment(2014) SOUSA, Rafael T. de; ZANETTI, Marcus V.; GATTAZ, Wagner F.; MACHADO-VIEIRA, Rodrigo; TEIXEIRA, Antonio L.
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 Longitudinal Study of State-Dependent Microstructural Brain Changes in Bipolar Disorder: Preliminary Report(2012) ZANETTI, Marcus V.; MACHADO-VIEIRA, Rodrigo; DOSHI, Jimit; CHAIM, Tiffany M.; SERPA, Mauricio; SOUSA, Rafael T. de; GATTAZ, Wagner F.; DAVATZIKOS, Christos; BUSATTO, Geraldo F.Background: Recent findings from cross-sectional studies suggest that mood disorders might be associated with state-dependent microstructural brain changes. Nevertheless, no study to date has evaluated this hypothesis using a longitudinal within-subject design. Methods: Seven treatment-naïve patients with recent-onset bipolar disorder (BD) in the acute phase of their illness (i.e., acute depressive, mixed or manic episode) underwent 64- direction diffusion tensor imaging (DTI) at two time points: at baseline (T0) and after clinical response (T1). Seven age and gender matched controls were also studied at two different time points. The time interval between scans ranged from 6 to 8 weeks. Whole-brain fractional anisotropy (FA) and mean diffusivity (MD) indices were obtained through a new routine adequate for spatial normalization of tensor fields. Preliminary voxelwise comparisons of FA and MD maps were conducted at an exploratory p≤0.001 threshold (uncorrected). Only resulting clusters with a minimum of 10 voxels and located in the white matter were considered significant. Results: At baseline, BD patients showed a focus of MD reduction affecting the right superior longitudinal fasciculus (SLF) relative to controls. Both longitudinal within-group and time versus diagnosis analyses revealed the following significant findings in the BD group over time: FA decrease in the right inferior longitudinal fasciculus (ILF); and MD increase in the left SLF. Conclusions: These preliminary results suggest that dynamic MD changes affecting the SLF may underlie the acute manifestations of BD as well as the transition to mood stabilization. Lithium treatment might be associated to FA decrease in the right ILF.conferenceObject Refractoriness in Schizophrenia is not Associated with Cyp2d6 and Cyp2c19 Genotypes(2012) BILT, Martinus T. van de; PRADO, Carolina M.; OJOPI, Elida P. B.; ZANETTI, Marcus V.; LOCH, Alexandre A.; SOUSA, Rafael A. T.; MACHADO-VIEIRA, Rodrigo; GATTAZ, Wagner F.Background: All genes that encode the CYP450 enzymes are highly polymorphic, leading to different metabolic profiles. While for antidepressants it’s possible to make dose adjustments based on the CYP2D6 and CYP2C19 genotypes, there are currently no evidences validating genotype based adjustments for antipsychotics. Therefore, we aimed to investigate the hypothesis that the prevalence of ultra-rapid metabolizers of neuroleptics would be increased among refractory schizophrenia patients. Methods: 89 schizophrenia patients were enrolled and divided in two groups: 59 refractory patients according to IPAP algorithm (International Psychopharmacology Algorithm Project) and 30 non-refractory patients. Polymorphisms in CYP2D6 and CYP2C19 genes were evaluated by allelic discrimination using the TaqMan® system. The following alleles were investigated: CYP2D6*1, *2, *3, *4, *5, *6, *9, *10, *15, *17, *29, *35, *39, *40, *41 beyond copy number variations and alleles CYP2C19*1, *2, *3 and *17. The phenotypes were classified in extensive metabolizers (EMs), poor metabolizers (PMs), intermediary metabolizers (IMs) and ultra-rapid metabolizers (UMs). Results: The distribution of the CYP2D6 and CYP2C19 phenotypes were as follows: CYP2D6: - Non-refractory: 13.3%PM + IM, 86.6%EM and 0.0% UM - Refractory: 13.5%PM + IM, 86.4%EM and 0.0%UM CYP2C19: - Non-refractory: 16.6%PM + IM, 53.3%EM and 30.0% UM - Refractory: 27.1%PM + IM, 40.6%EM and 32.2%UM Statistical analysis showed no significant difference between the distribution of the CYP2D6 phenotypes (p=0.244) and CYP2C19 predicted phenotypes (p = 0.755) among the two groups. Conclusions: Our findings do not reinforce the inclusion of genotyping of these genes as a tool in the clinical decision making in refractory schizophrenia.conferenceObject 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.