MARTINUS THEODORUS VAN DE BILT

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Instituto de Psiquiatria, Hospital das Clínicas, Faculdade de Medicina - Médico
LIM/27 - Laboratório de Neurociências, Hospital das Clínicas, Faculdade de Medicina

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Autor: GATTAZ, Wagner F. ×

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  • article 11 Citação(ões) na Scopus
    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.
  • article 4 Citação(ões) na Scopus
    Increased platelet glycogen sysnthase kinase 3beta in first-episode psychosis
    (2018) JOAQUIM, Helena P. G.; ZANETTI, Marcus V.; SERPA, Mauricio H.; BILT, Martinus T. Van de; SALLET, Paulo C.; CHAIM, Tiffany M.; BUSATTO, Geraldo F.; GATTAZ, Wagner F.; TALIB, Leda L.
    Past studies have linked intracellular pathways related to psychotic disorders to the GSK3B enzyme. This study aimed to investigate GSK3B protein expression and phosphorylation in drug-naive first-episode psychosis patients (n = 43) at baseline and following symptom remission, and in healthy controls (n = 77). At baseline GSK3B total level was higher in patients (p < 0.001). In schizophrenia spectrum patients (n = 25) GSK3B total and phosphorylated levels were higher than in controls and patients with other non-affective psychotic disorders (n = 18) (p < 0.001; p = 0.027; p = 0.05 respectively). No enzyme changes were found after clinical remission. The implication of this finding for the biology of psychoses warrants further studies to clarify whether increased GSK3B may be useful as a biomarker for psychosis in general, and schizophrenia in particular.
  • conferenceObject
    Anti-psychotic Treatment Decreased iPLA2 Activity in First Episode Drug Naive Patients (DNP)
    (2014) TALIB, Leda Leme; JOAQUIM, Helena P. G.; SERPA, Mauricio H.; BILT, Martinus Th van de; BUSATTO, Geraldo; ZANETTI, Marcus V.; GATTAZ, Wagner F.
  • article 101 Citação(ões) na Scopus
    Lithium increases plasma brain-derived neurotrophic factor in acute bipolar mania: A preliminary 4-week study
    (2011) SOUSA, Rafael T. de; BILT, Martinus T. van de; DINIZ, Breno S.; LADEIRA, Rodolfo B.; PORTELA, Luis V.; SOUZA, Diogo O.; FORLENZA, Orestes V.; GATTAZ, Wagner F.; MACHADO-VIEIRA, Rodrigo
    Several studies have suggested an important role for brain-derived neurotrophic factor (BDNF) in the pathophysiology and therapeutics of bipolar disorder (BPD). The mechanisms underlying the therapeutic effects of lithium in BPD seem to involve a direct regulation of neurotrophic cascades. However, no clinical study evaluated the specific effects of lithium on BDNF levels in subjects with BPD. This study aims to investigate the effects of lithium monotherapy on BDNF levels in acute mania. Ten subjects with bipolar I disorder in a manic episode were evaluated at baseline and after 28 days of lithium therapy. Changes in plasma BDNF levels and Young Mania Rating Scale (YMRS) scores were analyzed. A significant increase in plasma BDNF levels was observed after 28 days of therapy with lithium monotherapy (510.9 +/- 127.1 pg/mL) compared to pre-treatment (406.3 +/- 69.5 pg/mL) (p = 0.03). Although it was not found a significant association between BDNF levels and clinical improvement (YMRS), 87% of responders presented an increase in BDNF levels after treatment with lithium. These preliminary data showed lithium's direct effects on BDNF levels in bipolar mania, suggesting that short-term lithium treatment may activate neurotrophic cascades. Further studies with larger samples and longer period may confirm whether this biological effect is involved in the therapeutic efficacy of lithium in BPD.
  • 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.
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    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
    Increased Glycogen Synthase Kinase-3B (GSK3B) Expression in Platelets of First Onset Psychosis Non-affective Patients
    (2014) JOAQUIM, Helena P. G.; TALIB, Leda L.; BILT, Martinus Th van de; ZANETTI, Marcus V.; BUSATTO, Geraldo; SERPA, Mauricio H.; GATTAZ, Wagner F.
  • article 3 Citação(ões) na Scopus
    Application of Lipidomics in Psychiatry: Plasma-Based Potential Biomarkers in Schizophrenia and Bipolar Disorder
    (2023) COSTA, Alana C.; RICA, Larissa B.; BILT, Martinus van de; ZANDONADI, Flavia S.; GATTAZ, Wagner F.; TALIB, Leda L.; SUSSULINI, Alessandra
    In this study, we obtained a lipidomic profile of plasma samples from drug-naive patients with schizophrenia (SZ) and bipolar disorder (BD) in comparison to healthy controls. The sample cohort consisted of 30 BD and 30 SZ patients and 30 control individuals. An untargeted lipidomics strategy using liquid chromatography coupled with high-resolution mass spectrometry was employed to obtain the lipid profiles. Data were preprocessed, then univariate (t-test) and multivariate (principal component analysis and orthogonal partial least squares discriminant analysis) statistical tools were applied to select differential lipids, which were putatively identified. Afterward, multivariate receiver operating characteristic tests were performed, and metabolic pathway networks were constructed, considering the differential lipids. Our results demonstrate alterations in distinct lipid pathways, especially in glycerophospholipids, sphingolipids and glycerolipids, between SZ and BD patients. The results obtained in this study may serve as a basis for differential diagnosis, which is crucial for effective treatment and improving the quality of life of patients with psychotic disorders.
  • article 10 Citação(ões) na Scopus
    Early improvement of psychotic symptoms with lithium monotherapy as a predictor of later response in mania
    (2012) SOUSA, Rafael T. de; BUSNELLO, Joao V.; FORLENZA, Orestes V.; ZANETTI, Marcus V.; SOEIRO-DE-SOUZA, Marcio G.; BILT, Martinus T. van de; MORENO, Ricardo A.; ZARATE JR., Carlos A.; GATTAZ, Wagner F.; MACHADO-VIEIRA, Rodrigo
    Although lithium has been the first line agent in the treatment of bipolar disorder (BD), few studies have evaluated lithium's efficacy in mania with psychosis and its association with later response. Furthermore, given the widespread concern about antipsychotic side effects, answering a question about whether lithium alone can manage to treat both psychotic and non-psychotic mania seems a very relevant one. The present study addresses the antipsychotic efficacy of lithium monotherapy in acute mania and early improvement of psychotic symptoms as a predictor of later response of manic symptoms. Forty-six patients presenting a manic episode (32 with psychotic features and 14 subjects without psychotic features) were treated for 4 weeks with lithium monotherapy and evaluated weekly using the Young Mania Rating Scale (YMRS). Subjects with rapid cycling, substance abuse/dependence, or mixed episodes were excluded. The overall antimanic efficacy of lithium in psychosis vs. non-psychosis groups was evaluated. In addition, early improvement of psychotic symptoms and its prediction of subsequent response (>50% decrease in total YMRS scores) or remission were evaluated. Lithium showed a similar efficacy in both psychosis and non-psychosis mania. Early improvement of psychotic symptoms was associated with clinical response and remission at endpoint.
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    Neuroanatomical Pattern Classification in Unmedicated First-Episode Psychosis: Influence of Different Imaging Feature Selection
    (2012) SERPA, Mauricio H.; ZANETTI, Marcus V.; VAROL, Erdem; CHAIM, Tiffany M.; GAONKAR, Bilwaj; DOSHI, Jimit; BILT, Martinus T. van de; SALLET, Paulo C.; GATTAZ, Wagner F.; BUSATTO, Geraldo F.; DAVATZIKOS, Christos
    Background: The application of pattern classification approaches is thought to hold promise as an auxiliary tool to aid clinical diagnoses in psychiatric practice. However, few neuroimaging studies to date have investigated the usefulness of these methods in the evaluation of schizophrenia and related psychoses. Moreover, most of patients enrolled in such studies were already receiving antipsychotic medication, an important confounding factor for brain measures. Methods: Eleven treatment-naïve first-episode psychosis (FEP) individuals and 19 controls underwent T1-MPRAGE and 64-direction diffusion tensor imaging (DTI) acquisitions using a 1.5T MRI scanner. Volumetric maps of gray matter, white matter and ventricular compartments were generated through a robust routine of deformation-based morphometry. A new approach adequate for spatial normalization of tensor fields was used to generate fractional anisotropy (FA) and mean diffusivity maps. A multivariate classifier based on support vector machine was employed to identify the best set of morphological and DTI features that discriminate FEP individuals from controls. Diagnostic measures were obtained through ROC curve analyses. Results: The discrimination performance of the classifier varied according to the combination of different features, and the greater area under the curve value (0.68) was obtained when the FA map was employed in isolation. The resulting spatial map revealed a predominant pattern of increased FA in the right parietal region of FEP patients relative to controls, which may reflect differences in functional activity. Conclusions: This preliminary report suggests that FA indices afford the best discrimination between treatment-naïve FEP patients and controls relative to other morphometric and DTI features.