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 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.- 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.
- Cognitive impairment in late-life bipolar disorder is not associated with Alzheimer's disease pathological signature in the cerebrospinal fluid(2016) FORLENZA, Orestes V.; APRAHAMIAN, Ivan; RADANOVIC, Marcia; TALIB, Leda L.; CAMARGO, Marina Z. A.; STELLA, Florindo; MACHADO-VIEIRA, Rodrigo; GATTAZ, Wagner F.ObjectivesCognitive impairment is a common feature of late-life bipolar disorder (BD). Yet, there is limited information on the biological mechanisms associated with this process. It is uncertain whether cognitively impaired patients with BD may present the Alzheimer's disease (AD) bio-signature in the cerebrospinal fluid (CSF), defined as a combination of low concentrations of the amyloid-beta peptide (A(1-42)) and high concentrations of total tau (T-tau) and tau phosphorylated at threonine 181 (P-tau). In this study, we sought to determine whether cognitive impairment in elderly patients with BD is associated with the AD CSF bio-signature. MethodsSeventy-two participants were enrolled in the study. The test group comprised older adults with BD and mild cognitive impairment (BD-MCI; n=16) and the comparison groups comprised patients with dementia due to AD (n=17), patients with amnestic MCI (aMCI; n=14), and cognitively healthy older adults (control group; n=25). CSF samples were obtained by lumbar puncture and concentrations of A(1-42), T-tau and P-tau were determined. ResultsCSF concentrations of all biomarkers were significantly different in the AD group compared to all other groups, but did not differentiate BD-MCI subjects from aMCI subjects and controls. BD-MCI patients had a non-significant reduction in CSF A(1-42) compared to controls, but this was still higher than in the AD group. Concentrations of T-tau and P-tau in BD-MCI patients were similar to those in controls, and significantly lower than those in AD. ConclusionsCognitively impaired patients with BD do not display the so-called AD bio-signature in the CSF. We therefore hypothesize that cognitive deterioration in BD is not associated with the classical pathophysiological mechanisms observed in AD, i.e., amyloid deposition and hyperphosphorylation of microtubule-associated tau protein.
- Glycogen Synthase Kinase-3 beta: Variation over Time and the Possible Association with Mood and Cognition in Healthy Individuals(2016) MUNKHOLM, Klaus; LENSKJOLD, Toke; JACOBY, Anne Sophie; MISKOWIAK, Kamilla Woznica; VINBERG, Maj; JOAQUIM, Helena Giroud Passarelli; TALIB, Leda Leme; GATTAZ, Wagner Farid; KESSING, Lars VedelEvidence indicates a role for glycogen synthase kinase-3 beta (GSK-3 beta) in the pathophysiology of mood disorders and in cognitive disturbances; however, the natural variation in GSK-3 beta activity over time is unknown. We aimed to investigate GSK-3 beta activity over time and its possible correlation with emotional lability, subjective mood fluctuations and cognitive function in healthy individuals. Thirty-seven healthy subjects were evaluated with neuropsychological tests and blood samples at baseline and 12-week follow-up. Total GSK-3 beta and serine-9-phosphorylated GSK-3 beta in peripheral blood mononuclear cells were quantitated using enzyme immunometric assays. The activity of GSK-3 beta (serine-9-phosphorylated GSK-3 beta/total GSK-3 beta) was lower at baseline compared with follow-up. No significant mean change over time was observed in levels of total GSK-3 beta and serine-9-phosphorylated GSK-3 beta. Exploratory analysis revealed lower activity of GSK-3 beta in spring and summer compared with the fall season. No correlation was observed between GSK-3 beta activity and emotional lability, subjective mood fluctuations or cognitive function. The results suggest that intra- and interindividual variation in GSK-3 beta activity over time could contribute to the heterogeneity of findings in clinical studies. The stability of GSK-3 beta activity and the role of potential moderators of GSK-3 beta activity warrant further investigation. Clinical studies of GSK-3 beta should consider including repeated measures of both cases and healthy individuals. (C) 2016 S. Karger AG, Basel
- Lithium activates brain phospholipase A2 and improves memory in rats: implications for Alzheimer's disease(2016) MURY, Fabio B.; SILVA, Weber C. da; BARBOSA, Nadia R.; MENDES, Camila T.; BONINI, Juliana S.; SARKIS, Jorge Eduardo Souza; CAMMAROTA, Martin; IZQUIERDO, Ivan; GATTAZ, Wagner F.; DIAS-NETO, EmmanuelPhospholipase A2 (Pla2) is required for memory retrieval, and its inhibition in the hippocampus has been reported to impair memory acquisition in rats. Moreover, cognitive decline and memory deficits showed to be reduced in animal models after lithium treatment, prompting us to evaluate possible links between Pla2, lithium and memory. Here, we evaluated the possible modulation of Pla2 activity by a long-term treatment of rats with low doses of lithium and its impact in memory. Wistar rats were trained for the inhibitory avoidance task, treated with lithium for 100 days and tested for perdurability of long-term memory. Hippocampal samples were used for quantifying the expression of 19 brain-expressed Pla2 genes and for evaluating the enzymatic activity of Pla2 using group-specific radio-enzymatic assays. Our data pointed to a significant perdurability of long-term memory, which correlated with increased transcriptional and enzymatic activities of certain members of the Pla2 family (iPla2 and sPla2) after the chronic lithium treatment. Our data suggest new possible targets of lithium, add more information on its pharmacological activity and reinforce the possible use of low doses of lithium for the treatment of neurodegenerative conditions such as the Alzheimer's disease.
- Home-Based Psychiatric Outpatient Care Through Videoconferencing for Depression: A Randomized Controlled Follow-Up Trial(2016) HUNGERBUEHLER, Ines; VALIENGO, Leandro; LOCH, Alexandre A.; ROSSLER, Wulf; GATTAZ, Wagner F.Background: There is a tremendous opportunity for innovative mental health care solutions such as psychiatric care through videoconferencing to increase the number of people who have access to quality care. However, studies are needed to generate empirical evidence on the use of psychiatric outpatient care via videoconferencing, particularly in low-and middle-income countries and clinically unsupervised settings. Objective: The objective of this study was to evaluate the effectiveness and feasibility of home-based treatment for mild depression through psychiatric consultations via videoconferencing. Methods: A randomized controlled trial with a 6-and 12-month follow-up including adults with mild depression treated in an ambulatory setting was conducted. In total, 107 participants were randomly allocated to the videoconferencing intervention group (n=53) or the face-to-face group (F2F; n=54). The groups did not differ with respect to demographic characteristics at baseline. The F2F group completed monthly follow-up consultations in person. The videoconferencing group received monthly follow-up consultations with a psychiatrist through videoconferencing at home. At baseline and after 6 and 12 months, in-person assessments were conducted with all participants. Clinical outcomes (severity of depression, mental health status, medication course, and relapses), satisfaction with treatment, therapeutic relationship, treatment adherence (appointment compliance and dropouts), and medication adherence were assessed. Results: The severity of depression decreased significantly over the 12-month follow-up in both the groups. There was a significant difference between groups regarding treatment outcomes throughout the follow-up period, with better results in the videoconferencing group. There were 4 relapses in the F2F group and only 1 in the videoconferencing group. No significant differences between groups regarding mental health status, satisfaction with treatment, therapeutic relationship, treatment adherence, or medication compliance were found. However, after 6 months, the rate of dropouts was significantly higher in the F2F group (18.5% vs 5.7% in the videoconferencing group, P<. 05). Conclusions: Psychiatric treatment through videoconferencing in clinically unsupervised settings can be considered feasible and as effective as standard care (in-person treatment) for depressed outpatients with respect to clinical outcomes, patient satisfaction, therapeutic relationship, treatment adherence, and medication compliance. These results indicate the potential of telepsychiatry to extend access to psychiatric care to remote and underserved populations.
- A Selective Association between Central and Peripheral Lithium Levels in Remitters in Bipolar Depression: A 3T-Li-7 Magnetic Resonance Spectroscopy Study(2016) MACHADO-VIEIRA, R.; OTADUY, M. C.; ZANETTI, M. V.; SOUSA, R. T. De; DIAS, V. V.; LEITE, C. C.; FORLENZA, O. V.; BUSATTO, G. F.; SOARES, J. C.; GATTAZ, W. F.ObjectiveThe objective of this study was to evaluate brain lithium levels using Li-7 magnetic resonance spectroscopy after 6 weeks of lithium therapy in bipolar depression to test the hypothesis that brain and plasma lithium are correlated. It was also tested whether responders and remitters have different pharmacokinetics, blood and brain lithium levels (ratio) compared with those presenting suboptimal antidepressant improvement. MethodTwenty-three patients with bipolar disorder (I and II) during depressive episodes were included and followed up for 6 weeks at the University of Sao Paulo using flexible dose of lithium (450-900 mg/day). Sixteen patients were drug-naive. At endpoint, patients underwent a Li-7-MRS scan and brain lithium concentrations were calculated. ResultsA significant association between central and peripheral lithium levels was found only in remitters (r = 0.7, P = 0.004) but not in non-remitters (r = -0.12, P = 0.76). Also, brain lithium (but not plasma) was inversely correlated with age (r = -0.46, P = 0.025). Plasma lithium did not correlate with any clinical outcome, lithium dosage or adverse effects. ConclusionThese findings suggest that non-remitters may not transport lithium properly to the brain, which may underlie treatment resistance to lithium in BD. Future studies with Li-7-MRS integrated with the evaluation of blood-brain barrier transport mechanisms and longitudinal clinical outcomes in BD and aging are warranted.
- Lithium Distinctly Modulates the Secretion of Pro- and Anti-Inflammatory Interleukins in Co-Cultures of Neurons and Glial Cells at Therapeutic and Sub-Therapeutic Concentrations(2016) DE-PAULA, Vanessa J.; KERR, Daniel S.; SCOLA, Gustavo; GATTAZ, Wagner F.; FORLENZA, Orestes V.Lithium is associated with various effects on immune functions, some of which are still poorly understood. The roles of many cytokines have been characterized in a variety of neurodevelopmental processes including neurogenesis, neuronal and glial cell migration, proliferation, differentiation, synaptic maturation and synaptic pruning. This work aims to evaluate the effects of different doses of lithium (0.02; 0.2 and 2mM) on the secretion of cytokines in co-cultures of cortical and hippocampal neurons with glial cells. Our results indicate that chronic treatment with lithium chloride at sub-therapeutic concentrations are able to modify the secretion of pro-and anti-inflammatory interleukins in co-cultures of cortical and hippocampal neurons with glial cells.
- Pioneering ambient mass spectrometry imaging in psychiatry: Potential for new insights into schizophrenia(2016) VENDRAMINI, Pedro H.; GATTAZ, Wagner F.; SCHMITT, Andrea; FALKAI, Peter; EBERLIN, Marcos N.; MARTINS-DE-SOUZA, DanielUnderstanding the molecular basis of schizophrenia is essential for disease management, and several molecular biology tools have been employed for this purpose. Mass spectrometry, which is used mostly in proteomic and metabolomic studies, is one such tool. Here, we present the first psychiatric study to use mass spectrometry imaging (MSI) with desorption electrospray ionization (DESI). Preparation of samples for use with DESI-MSI is remarkably simple and quick and preserves the spatial distribution of analytes. By using this tool, we found differences in the phospholipid content in schizophrenia postmortem brains. These results validate both the role of phospholipids in schizophrenia and the value of this MS tool in furthering the understanding of the molecular aspects of the disease.
- cytochrome P450 genotypes are not associated with refractoriness to antipsychotic treatment (vol 168, pg 587, 2015)(2016) BILT, M. T. van de; PRADO, C. M.; OJOPI, E. P. B.; SOUSA, R. T. de; LOCH, A. A.; ZANETTI, M. V.; TALIB, L. L.; GATTAZ, W. F.