RAFAEL AUGUSTO TEIXEIRA DE SOUSA

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

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Assunto: Neurosciences ×

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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, Rodrigo
    Background: 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, Rodrigo
    Background: 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.
  • article 13 Citação(ões) na Scopus
    Regulation of leukocyte tricarboxylic acid cycle in drug-naive Bipolar Disorder
    (2015) SOUSA, Rafael T. de; STRECK, Emilio L.; FORLENZA, Orestes V.; BRUNONI, Andre R.; ZANETTI, Marcus V.; FERREIRA, Gabriela K.; DINIZ, Breno S.; PORTELA, Luis V.; CARVALHO, Andre F.; ZARATE JR., Carlos A.; GATTAZ, Wagner F.; MACHADO-VIEIRA, Rodrigo
    Several lines of evidence suggest a role for mitochondrial dysfunction in the pathophysiology of bipolar disorder (BD). The tricarboxylic acid cycle (TCA cycle) is fundamental for mitochondrial energy production and produces substrates used in oxidative phosphorylation by the mitochondrial electron transport chain. The activity of the key TCA cycle enzymes citrate synthase, malate dehydrogenase, and succinate dehydrogenase has never been evaluated in BD. In the present study, these enzymes were assayed from leukocytes of drug-naive BD patients in a major depressive episode (n = 18) and compared to 24 age-matched healthy controls. Drug-naive BD patients did not show differences in activities of citrate synthase (p = 0.79), malate dehydrogenase (p = 0.17), and succinate dehydrogenase (p = 0.35) compared with healthy controls. No correlation between any TCA cycle enzyme activity and severity of depressive symptoms was observed. Overall, these data suggest that the activities of the TCA cycle enzymes are not altered in major depressive episodes of recent-onset BD, which may support the concept of illness staging and neuroprogression in BD.
  • article 34 Citação(ões) na Scopus
    Genetic Studies on the Tripartite Glutamate Synapse in the Pathophysiology and Therapeutics of Mood Disorders
    (2017) SOUSA, Rafael T. de; LOCH, Alexandre A.; CARVALHO, Andre F.; BRUNONI, Andre R.; HADDAD, Marie Reine; HENTER, Ioline D.; ZARATE JR., Carlos A.; MACHADO-VIEIRA, Rodrigo
    Both bipolar disorder (BD) and major depressive disorder (MDD) have high morbidity and share a genetic background. Treatment options for these mood disorders are currently suboptimal for many patients; however, specific genetic variables may be involved in both pathophysiology and response to treatment. Agents such as the glutamatergic modulator ketamine are effective in treatment-resistant mood disorders, underscoring the potential importance of the glutamatergic system as a target for improved therapeutics. Here we review genetic studies linking the glutamatergic system to the pathophysiology and therapeutics of mood disorders. We screened 763 original genetic studies of BD or MDD that investigated genes encoding targets of the pathway/mediators related to the so-called tripartite glutamate synapse, including pre- and post-synaptic neurons and glial cells; 60 papers were included in this review. The findings suggest the involvement of glutamate-related genes in risk for mood disorders, treatment response, and phenotypic characteristics, although there was no consistent evidence for a specific gene. Target genes of high interest included GRIA3 and GRIK2 (which likely play a role in emergent suicidal ideation after antidepressant treatment), GRIK4 (which may influence treatment response), and GRM7 (which potentially affects risk for mood disorders). There was stronger evidence that glutamate-related genes influence risk for BD compared with MDD. Taken together, the studies show a preliminary relationship between glutamate-related genes and risk for mood disorders, suicide, and treatment response, particularly with regard to targets on metabotropic and ionotropic receptors.
  • 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
    MRI investigation of a 6-week trial of lithium in medication-free patients with bipolar depression
    (2014) ZANETTI, M. V.; OTADUY, M. C. G.; SOUSA, R. T. de; SOEIRO-DE-SOUZA, M. G.; CHAIM, K. T.; GATTAZ, W. F.; BUSATTO, G. F.; LEITE, C. C.; MACHADO-VIEIRA, R.
  • 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).
  • article 30 Citação(ões) na Scopus
    Elevated neurotrophin-3 and neurotrophin 4/5 levels in unmedicated bipolar depression and the effects of lithium
    (2015) LOCH, Alexandre A.; ZANETTI, Marcus V.; SOUSA, Rafael T. de; CHAIM, Tiffany M.; SERPA, Mauricio H.; GATTAZ, Wagner F.; TEIXEIRA, Antonio L.; MACHADO-VIEIRA, Rodrigo
    Background: Bipolar disorder (BD) has been associated with diverse abnormalities in neural plasticity and cellular resilience. Neurotrophin-3 (NT-3) and neurotrophin-4/5 (NT-4/5) support synaptic neuronal survival and differentiation. NT-3 and NT-4/5 levels were found to be altered in BD, potentially representing a physiological response against cellular stress. However, the use of psychopharmacological agents and heterogeneous mood states may constitute important biases in such studies. Thus, we aimed to assess NT-3 and NT-4/5 levels in medication-free BD type I or II individuals in a current depressive episode, before and after 6weeks of lithium monotherapy and matched with healthy controls. Methods: Twenty-three patients with BD type I or II during a depressive episode and 28 healthy controls were studied. Patients were required to have a 21-item Hamilton Depression Rating Scale score >= 18 and had not undergone any psychopharmacological treatment for at least 6 weeks prior to study entry. Patients were treated with lithium for 6 weeks and plasma NT-3 and NT-4/5 levels were determined at baseline and end point using ELISA method. Results: Baseline plasma levels of both NT-3 and NT-4/5 were significantly increased in acutely depressed BD subjects in comparison to healthy controls (p = 0.040 and 0.039, respectively). The NT-3 and NT-4/5 levels did not significantly change after lithium treatment. NT-3 and NT-4/5 levels were positively correlated to illness duration in BD (p = 0.032 and 0.034, respectively). Conclusion: Our findings suggest that NT-3 and NT-4/5 levels are increased in the depressive phase of BD, which seems directly associated with illness duration. The increased levels of NT-3 and NT-4/5 may underlie a biological response to cellular stress associated with the course of BD.
  • article 28 Citação(ões) na Scopus
    Bimodal Effect of Lithium Plasma Levels on Hippocampal Glutamate Concentrations in Bipolar II Depression: A Pilot Study
    (2015) ZANETTI, Marcus V.; OTADUY, Maria C.; SOUSA, Rafael T. de; GATTAZ, Wagner F.; BUSATTO, Geraldo F.; LEITE, Claudia C.; MACHADO-VIEIRA, Rodrigo
    Background: The hippocampus has been highly implicated in the pathophysiology of bipolar disorder (BD). Nevertheless, no study has longitudinally evaluated hippocampal metabolite levels in bipolar depression under treatment with lithium. Methods: Nineteen medication-free BD patients (78.9% treatment-naive and 73.7% with BD type II) presenting an acute depressive episode and 17 healthy controls were studied. Patients were treated for 6 weeks with lithium in an open-label trial. N-acetyl aspartate (NAA), creatine, choline, myo-Inositol, and glutamate levels were assessed in the left hippocampus before (week 0) and after (week 6) lithium treatment using 3T proton magnetic resonance spectroscopy (1H-MRS). The metabolite concentrations were estimated using internal water as reference and voxel segmentation for partial volume correction. Results: At baseline, acutely depressed BD patients and healthy controls exhibited similar hippocampal metabolites concentrations, with no changes after 6 weeks of lithium monotherapy. A significant correlation between antidepressant efficacy and increases in NAA concentration over time was observed. Also, there was a significant positive correlation between the changes in glutamate concentrations over follow-up and plasma lithium levels at endpoint. Mixed effects model analysis revealed a bimodal effect of lithium plasma levels in hippocampal glutamate concentrations: levels of 0.2 to 0.49 mmol/L (n=9) were associated with a decrease in glutamate concentrations, whereas the subgroup of BD subjects with ""standard"" lithium levels (>= 0.50 mmol/L; n = 10) showed an overall increase in glutamate concentrations over time. Conclusions: These preliminary results suggest that lithium has a bimodal action in hippocampal glutamate concentration depending on the plasma levels.
  • article 66 Citação(ões) na Scopus
    Decreased AKT1/mTOR pathway mRNA expression in short-term bipolar disorder
    (2015) MACHADO-VIEIRA, Rodrigo; ZANETTI, Marcus V.; TEIXEIRA, Antonio L.; UNO, Miyuki; VALIENGO, Leandro L.; SOEIRO-DE-SOUZA, Marcio G.; OBA-SHINJO, Sueli M.; SOUSA, Rafael T. de; ZARATE JR., Carlos. A.; GATTAZ, Wagner F.; MARIE, Suety K. N.
    Strong evidence implicates intracellular signaling cascades dysfunction in the pathophysiology of Bipolar Disorder (BD). Regulation of AKT/mTOR pathway is a critical signaling pathway in synaptic neurotransmission and plasticity, also modulating cell proliferation and migration. Gene expression of the AKT/mTOR pathway was assessed in 25 BD (DSM-IV-TR criteria) unmedicated depressed individuals at baseline and after 6 weeks of lithium therapy and 31 matched healthy controls. Decreases in blood AKT/ and mTOR mRNA expression, as well as in BAD/BCL-2 expression ratio were observed in short-term BD patients during depressive episodes in comparison to healthy controls. There was no significant change in the expression of AKT1, mTOR, BCL-2, BAD and NDUFA6 after lithium therapy in the total group of BD subjects. However, the changes in AKT1 expression after lithium treatment were positively correlated with depression improvement. An integrated activity within this pathway was observed at both baseline and post-treatment. The present results support an integrated AKT/mTOR signaling pathway activity in a similar fashion to the described in previous human postmortem and rodents brain studies. Overall, the results reinforce a role for AKT1 and mTOR in the pathophysiology of BD and support the relevance of blood mRNA expression as a valid surrogate biological source to study brain intracellular signaling cascades changes and convergent molecular pathways in psychiatric disorders.