WAGNER FARID GATTAZ
Projetos de Pesquisa
Unidades Organizacionais
Departamento de Psiquiatria, Faculdade de Medicina - Docente
LIM/27 - Laboratório de Neurociências, Hospital das Clínicas, Faculdade de Medicina - Líder
LIM/27 - Laboratório de Neurociências, Hospital das Clínicas, Faculdade de Medicina - Líder
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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.- Higher transcription alleles of the MAOA-uVNTR polymorphism are associated with higher seizure frequency in temporal lobe epilepsy(2019) VINCENTIIS, Silvia; ALCANTARA, Juliana; RZEZAK, Patricia; KERR, Daniel; SANTOS, Bernardo dos; ALESSI, Ruda; LINDEN, Helio van der; ARRUDA, Francisco; CHAIM-AVANCINI, Tiffany; SERPA, Mauricio; BUSATTO, Geraldo; GATTAZ, Wagner; DEMARQUE, Renata; VALENTE, Kette D.Background: There is evidence of an imbalance in the neuromodulatory system mediated by serotonin (5-HT) in patients with drug-resistant temporal lobe epilepsy (TLE). This study analyzed the monoamine oxidase A promoter variable number of tandem repeats (MAOA-uVNTR) polymorphism in patients with temporal lobe epilepsy with hippocampal sclerosis (TLE-HS). Therefore, we assessed the association between this genetic variant and seizure predisposition and severity in patients with TLE-HS. Methods: One hundred nineteen patients with TLE-HS and 113 healthy volunteers were assessed. First, we genotyped all individuals for the MAOA-uVNTR genetic polymorphism. Second, we compared patients and controls and evaluated clinical variants of epilepsy. Results: There was no difference between the TLE-HS and control groups regarding genotypic and allelic distributions of MAOA-uVNTR polymorphism (p = 1.000). Higher transcription alleles of the MAOA-uVNTR were associated with higher seizure frequency (p = 0.032) and bilateral tonic-clonic seizures (p = 0.016). Conclusions: In a selected group of patients with TLE-HS, the polymorphism MAOA-uVNTR was associated with some aspects of epilepsy severity, namely seizure frequency and bilateral tonic-clonic seizures.
- Increased Brain Lactate During Depressive Episodes and Reversal Effects by Lithium Monotherapy in Drug-Naive Bipolar Disorder A 3-T H-1-MRS Study(2017) MACHADO-VIEIRA, Rodrigo; ZANETTI, Marcus V.; OTADUY, Maria C.; SOUSA, Rafael T. De; SOEIRO-DE-SOUZA, Marcio G.; COSTA, Alana C.; CARVALHO, Andre F.; LEITE, Claudia C.; BUSATTO, Geraldo F.; ZARATE JR., Carlos A.; GATTAZ, Wagner F.Objective: Mitochondrial dysfunction and energy metabolism impairment are key components in the pathophysiology of bipolar disorder (BD) and may involve a shift from aerobic to anaerobic metabolism. Measurement of brain lactate in vivo using protonmagnetic resonance spectroscopy (H-1-MRS) represents an important tool to evaluate mitochondrial and metabolic dysfunction during mood episodes, as well as to monitor treatment response. To date, very few studies have quantified brain lactate in BD. In addition, no study has longitudinally evaluated lactate using H-1-MRS during depressive episodes or its association with mood stabilizer therapy. This study aimed to evaluate cingulate cortex (CC) lactate using 3-T H-1-MRS during acute depressive episodes in BD and the possible effects induced by lithium monotherapy. Methods: Twenty medication-free outpatients with short length of BD (80% drug-naive) in a current major depressive episode were matched with control subjects. Patients were treated for 6 weeks with lithium monotherapy at therapeutic doses in an open-label trial (blood level, 0.48 +/- 0.19 mmol/L). Cingulate cortex lactate was measured before (week 0) and after lithium therapy (week 6) using H-1-MRS. Antidepressant efficacy was assessed with the 21-item Hamilton Depression Rating Scale as the primary outcome. Results: Subjects with BD depression showed a significantly higher CC lactate in comparison to control subjects. Furthermore, a significant decrease in CC lactate was observed after 6 weeks of lithium treatment compared with baseline (P = 0.002). CC Lactate levels was associated with family history of mood disorders and plasma lithium levels. Conclusions: This is the first report of increased CC lactate in patients with bipolar depression and lower levels after lithium monotherapy for 6 weeks. These findings indicate a shift to anaerobic metabolism and a role for lactate as a state marker during mood episodes. Energy and redox dysfunction may represent key targets for lithium's therapeutic actions.
- Lithium efficacy in bipolar depression with flexible dosing: A six-week, open-label, proof-of-concept study(2014) MACHADO-VIEIRA, Rodrigo; ZANETTI, Marcus V.; SOUSA, Rafael T. De; SOEIRO-DE-SOUZA, Marcio G.; MORENO, Ricardo A.; BUSATTO, Geraldo F.; GATTAZ, Wagner F.Lithium has a narrow therapeutic index with a subtle balance between effectiveness and adverse effects. Current guidelines recommend the use of lithium as a treatment for acute bipolar depression; however, the therapeutic range for the treatment has not been fully defined. Recently, the adjunctive lower lithium dose in bipolar depression has revealed potential efficacy; however, no study has investigated it predominantly in monotherapy. In this open-label, proof-of-concept study, 31 individuals with bipolar disorder during a depressive episode were randomized and 29 were followed up for six weeks with flexible lithium dosing. All subjects had a 21-item Hamilton Rating Scale for Depression (HAM-D) score of >= 18 at baseline. Subjects were divided into two groups, with higher (Li >= 0.5 mEq/l) or lower (Li <0.5 mEq/l) blood lithium levels. Response and remission rates were evaluated using the HAM-D scores. Following 6 weeks of lithium treatment, the remission rate for all patients was 62.0%. The plasma lithium levels did not impact the clinical response. However, subjects with higher blood lithium levels had an increased prevalence of nausea, restlessness, headaches and cognitive complaints. The results indicate that the lithium dose for the treatment of bipolar depression in an individual should be based on the clinical efficacy and side-effects. In the context of personalized psychiatric treatments, it is necessary to evaluate the therapeutic action of lithium with individual regimens in order to develop more tolerable and effective treatment approaches.
conferenceObject The Role Of Dopamine Transporter Intron 8 VNTR Polymorphism In The Occurrence Of Depression In Temporal Lobe Epilepsy(2019) VINCENTIIS, S.; ALCANTARA, J.; RZEZAK, P.; KERR, D.; GATTAZ, W.; LINDEN JUNIOR, H. van der; ARRUDA, F.; SANTOS, B. dos; CHAIM-AVANCINI, T.; SERPA, M.; FERNANDES, F.; MORENO, R. A.; BUSATTO, G. F.; DEMARQUE, R.; VALENTE, K. D.; ALESSI, R.conferenceObject Distinct Glycogen Synthase Kinase 3 beta and Phospholipase A2 Expression Profiles in Bipolar I and II Disorders(2016) ZANETTI, Marcus V.; MACHADO-VIEIRA, Rodrigo; JOAQUIM, Helena P. G.; CHAIM, Tiffany M.; SERPA, Mauricio H.; SOUSA, Rafael T. de; GATTAZ, Wagner F.; BUSATTO, Geraldo F.; TALIB, Leda L.- 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.
- Association study of functional polymorphisms of dopaminergic pathway in epilepsy-related factors of temporal lobe epilepsy in Brazilian population(2018) ALCANTARA, J. A.; VINCENTIS, S.; KERR, D. S.; SANTOS, B. dos; ALESSI, R.; LINDEN JR., H. van der; CHAIM, T.; SERPA, M. H.; BUSATTO, G. F.; GATTAZ, W. F.; DEMARQUE, R.; VALENTE, K. D.Background and purposeThere are few data about the role of neurotransmission modulated by dopamine in epilepsy, especially temporal lobe epilepsy (TLE). This is the first study that aimed to analyze the dopaminergic polymorphisms in an etiologically homogeneous group of patients with TLE with hippocampal sclerosis. Selected polymorphisms were: (i) the most expressed D2-like receptors in the limbic system (DRD2/ANKK1 TAQ-1A, D4_VNTR and D4_rs1800955); (ii) the dopamine transporter (DAT) 3-untranslated region and intron 8; and (iii) two degrading enzymes regulating the synaptic activity, i.e. the main metabolizer of dopamine, catechol-O-methyltransferase, and monoamine oxidase A. MethodsWe assessed 119 patients with unequivocal TLE with hippocampal sclerosis and 112 healthy volunteers. Individuals were genotyped for the polymorphisms of the gene encoding dopaminergic pathway transporter DAT haplotype, dopaminergic receptors, catechol-O-methyltransferase and monoamine oxidase A. We also evaluated epilepsy-related factors (e.g. seizure frequency, age of onset, duration and status epilepticus). ResultsThere was no difference between the groups for the studied polymorphisms. The polymorphism DRD4_VNTR was associated with family history of epilepsy (P = 0.003), DRD2_rs1800497 was related to status epilepticus (P = 0.022), and intron 8 VNTR DAT was related to higher seizure frequency (P = 0.019) and family history of epilepsy (P = 0.011). ConclusionsOur findings demonstrated that polymorphisms of the dopaminergic pathway are associated with significant clinical features of this form of epilepsy, such as seizure frequency, family history of epilepsy and status epilepticus.
- Patterns of regional gray matter loss at different stages of schizophrenia: A multisite, cross-sectional VBM study in first-episode and chronic illness(2016) TORRES, Ulysses S.; DURAN, Fabio L. S.; SCHAUFELBERGER, Maristela S.; CRIPPA, Jose A. S.; LOUZA, Mario R.; SALLET, Paulo C.; KANEGUSUKU, Caroline Y. O.; ELKIS, Helio; GATTAZ, Wagner F.; BASSITT, Debora P.; ZUARDI, AntonioW.; HALLAK, Jaime Eduardo C.; LEITE, Claudia C.; CASTRO, Claudio C.; SANTOS, Antonio Carlos; MURRAY, Robin M.; BUSATTO, Geraldo F.Background: Structural brain abnormalities in schizophrenia have been repeatedly demonstrated in magnetic resonance imaging (MRI) studies, but it remains unclear whether these are static or progressive in nature. While longitudinalMRI studies have been traditionally used to assess the issue of progression of brain abnormalities in schizophrenia, information from cross-sectional neuroimaging studies directly comparing first-episode and chronic schizophrenia patients to healthy controls may also be useful to further clarify this issue. With the recent interest in multisite mega-analyses combining structural MRI data from multiple centers aiming at increased statistical power, the present multisite voxel-basedmorphometry (VBM) studywas carried out to examine patterns of brain structural changes according to the different stages of illness and to ascertainwhich (if any) of such structural abnormalities would be specifically correlated to potential clinical moderators, including cumulative exposure to antipsychotics, age of onset, illness duration and overall illness severity. Methods: Wegathered a large sample of schizophrenia patients (161, being 99 chronic and 62 first-episode) and controls (151) fromfour previousmorphometricMRI studies (1.5 T) carried out in the same geographical region of Brazil. Image processing and analyses were conducted using Statistical Parametric Mapping (SPM8) software with the diffeomorphic anatomical registration through exponentiated Lie algebra (DARTEL) algorithm. Group effects on regional gray matter (GM) volumes were investigated through whole-brain voxel-wise comparisons using General LinearModel Analysis of Co-variance (ANCOVA), always including total GMvolume, scan protocol, age and gender as nuisance variables. Finally, correlation analyseswere performed between the aforementioned clinical moderators and regional and global brain volumes. Results: First-episode schizophrenia subjects displayed subtle volumetric deficits relative to controls in a circumscribed brain regional network identified only in small volume-corrected (SVC) analyses (p < 0.05, FWE-corrected), including the insula, temporolimbic structures and striatum. Chronic schizophrenia patients, on the other hand, demonstrated an extensive pattern of regional GM volume decreases relative to controls, involving bilateral superior, inferior and orbital frontal cortices, right middle frontal cortex, bilateral anterior cingulate cortices, bilateral insulae and right superior and middle temporal cortices (p < 0.05, FWE-corrected over the whole brain). GM volumes in several of those brain regionswere directly correlated with age of disease onset on SVC analyses for conjoined (first-episode and chronic) schizophrenia groups. There were also widespread foci of significant negative correlation between duration of illness and relative GM volumes, but such findings remained significant only for the right dorsolateral prefrontal cortex after accounting for the influence of age of disease onset. Finally, significant negative correlations were detected between life-time cumulative exposure to antipsychotics and total GM and white matter volumes in schizophrenia patients, but no significant relationship was found between indices of antipsychotic usage and relative GM volume in any specific brain region. Conclusion: The above data indicate that brain changes associated with the diagnosis of schizophrenia are more widespread in chronic schizophrenia compared to first-episode patients. Our findings also suggest that relative GM volume deficits may be greater in (presumably more severe) cases with earlier age of onset, as well as varying as a function of illness duration in specific frontal brain regions. Finally, our results highlight the potentially complex effects of the continued use of antipsychotic drugs on structural brain abnormalities in schizophrenia, as we found that cumulative doses of antipsychotics affected brain volumes globally rather than selectively on frontal-temporal regions. (C) 2016 The Authors.
- A Longitudinal MRI-study of the Effects of Lithium on Cortical Thickness and Brain Volume and its association with Clinical Response in Bipolar Disorder(2019) COSTA, Sabrina C. da; ZANETTI, Marcus V.; SUCHTING, Robert; SOUZA, Rafael T. de; OTADUY, Maria C.; LEITE, Claudia C.; BUSATTO, Geraldo F.; GATTAZ, Wagner F.; SOARES, Jair C.; MACHADO-VIEIRA, Rodrigo