CAROLINA MARTINS DO PRADO
Projetos de Pesquisa
Unidades Organizacionais
LIM/27 - Laboratório de Neurociências, Hospital das Clínicas, Faculdade de Medicina
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- Epistasis between COMT Val(158)Met and DRD3 Ser(9)Gly polymorphisms and cognitive function in schizophrenia: genetic influence on dopamine transmission(2015) 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.Objective: To assess the relationship between cognitive function, a proposed schizophrenia endophenotype, and two genetic polymorphisms related to dopamine function, catechol-O-methyl transferase (COMT) Val(158)Met and dopamine receptor 3 (DRD3) Ser(9)Gly. Methods: Fifty-eight outpatients with schizophrenia/schizoaffective disorder and 88 healthy controls underwent neurocognitive testing and genotyping. Analyses of covariance (ANCOVAs) using age, sex, and years of education as covariates compared cognitive performance for the proposed genotypes in patients and controls. ANCOVAs also tested for the epistatic effect of COMT and DRD3 genotype combinations on cognitive performance. Results: For executive functioning, COMT Val/Val patients performed in a similar range as controls (30.70-33.26 vs. 35.53-35.67), but as COMT Met allele frequency increased, executive functioning worsened. COMT Met/Met patients carrying the DRD3 Ser/Ser genotype performed poorest (16.184 vs. 27.388-31.824). Scores of carriers of this COMT/DRD3 combination significantly differed from all DRD3 Gly/Gly combinations (p < 0.05), from COMT Val/Met DRD3 Ser/Gly (p = 0.02), and from COMT Val/Val DRD3 Ser/Ser (p = 0.01) in patients. It also differed significantly from all control scores (p < 0.001). Conclusion: Combined genetic polymorphisms related to dopamine neurotransmission might influence executive function in schizophrenia. Looking at the effects of multiple genes on a single disease trait (epistasis) provides a comprehensive and more reliable way to determine genetic effects on endophenotypes.
conferenceObject Genetic Polymorphisms Related to Dopamine, Serotonine and BDNF Might be Specific to Particular Symptom Dimensions in Schizophrenia(2012) LOCH, Alexandre A.; BIO, Danielle S.; BILT, Martinus T. van de; PRADO, Carolina M.; ZANETTI, Marcus V.; GATTAZ, Wagner F.Background: Schizophrenia is held to be result of multiple small-effect genes and their interplay with environment. Several of these genes have been discovered, but their exact role in the disease is unclear. The objective of this study is to assess relationship between genetic polymorphisms and specific symptom dimensions in schizophrenia. Methods: Fifty-three outpatients with schizophrenia from the Institute of Psychiatry, Sao Paulo,Brazil, were selected. Psychopathology was evaluated through SCID-I, PANSS and neuropsychological assessment. Genotyping was performed by real-time PCR allelic discrimination. Polymorphisms HTR2A-T102C,-rs6314 and -rs1928042, HTR2C-rs6318 and -rs3813929, DRD3-rs6280, BDNF-rs6265 and COMT-rs4680 were analyzed. Associations between genetic polymorphisms and psychopathology were measured. Factor analysis was performed between psychopathological measures yielding symptom dimensions. Generalized linear models were conducted between these dimensions and positively related genetic polymorphisms; models were repeated including cofactor “refractoriness”. Results: HTR2C(rs6318) genotype CC(ser/ser) and DRD3 genotype CC(gly/gly) were related to worst cognition(p=0.01-0.03). DRD3 genotype TT(ser/ser) was associated with negative symptoms(p=0.04-0.05). BDNF genotype GA(val/met) and COMT genotype GG(val/val) were associated with positive symptoms(p=0.00-0.04). Factor analysis yielded 7 symptom dimensions: cognition was related to DRD3 and HTR2C-rs6318 (B=1.01,p=0.00;B=-0.92,p=0.04,respectively). Disorganization-catatonia was related to BDNF and HTR2C-rs6318 (B=-0.62,p=0.05;B=1.01,p=0.03,respectively). Paranoid-influence delusions were related to DRD3, HTR2C-rs6318 and HTR2A-rs1928042 (B=-1.03,p=0.00;B=-1.31,p=0.00;B=-1.04,p=0.04,respectively). Other delusions/hallucinations were related to DRD3, HTR2C-rs3813929 and BDNF (B=-1.1,p=0.01;B=-1.00,p=0.03;B=0.80,p=0.01,respectively). Negative symptoms were related to refractoriness (B=1.10,p=0.00). Dimensions hallucinations/bizarre delusion and tactile hallucinations did not correlate with any predictor. Conclusions: Our study proposes that genetic polymorphisms might be specific in determining certain symptom dimensions in schizophrenia, suggesting differential underlying physiopathological mechanisms for them.conferenceObject ABCB1 and HTR2A Polymorphism may be Related to Treatment Response in a Sample of Mood Disorders Patients Undergoing Electroconvulsive Therapy(2015) BILT, Martinus T. van de; PRADO, Carolina M. do; NICOLA, Bruna V.; RIGONATTI, Luiz Felipe; TALIB, Leda L.; RIGONATTI, Sergio Paulo; GATTAZ, Wagner F.- CYP2C9 Intermediate and Poor Metabolizers are More Prevalent in a Sample of Refractory Mood Disorders Patients Undergoing ECT(2014) BILT, Martinus T. van de; PRADO, Carolina M. do; RIGONATTI, Luiz F.; RIGONATTI, Sergio P.; TALIB, Leda L.; GATTAZ, Wagner F.
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.- ABCB1 Polymorphism may be Related to Refractoriness in a Sample of Mood Disorders Patients Undergoing ECT(2014) PRADO, Carolina M. do; BILT, Martinus T. van de; RIGONATTI, Luiz F.; RIGONATTI, Sergio P.; TALIB, Leda L.; GATTAZ, Wagner F.