RAFAEL AUGUSTO TEIXEIRA DE SOUSA
Projetos de Pesquisa
Unidades Organizacionais
LIM/27 - Laboratório de Neurociências, Hospital das Clínicas, Faculdade de Medicina
43 resultados
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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.- 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.
- 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.
- 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 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, RodrigoBackground: 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.- 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, RodrigoSeveral 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.
- 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, RodrigoBoth 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.
- Lithium increases platelet serine-9 phosphorylated GSK-3 beta levels in drug-free bipolar disorder during depressive episodes(2015) SOUSA, Rafael T. de; ZANETTI, Marcus V.; TALIB, Leda L.; SERPA, Mauricio H.; CHAIM, Tiffany M.; CARVALHO, Andre F.; BRUNONI, Andre R.; BUSATTO, Geraldo F.; GATTAZ, Wagner E.; MACHADO-VIEIRA, RodrigoBackground: Glycogen synthase kinase-3 beta (GSK3 beta) is an intracellular enzyme directly implicated in several neural processes relevant to bipolar disorder (BD) pathophysiology. GSK3 beta is also an important target for lithium and antidepressants. When phosphorylated at serine-9, GSK3 beta becomes inactive. Few studies evaluated serine-9 phosphorylated GSK3 beta(phospho-GSK3 beta) levels in BD subjects in vivo and no study has assessed it specifically in bipolar depression. Also, the effect of lithium monotherapy on GSK3 beta has never been studied in humans. Methods: In 27 patients with bipolar depression, total GSK3 beta and phospho-GSK3 beta were assessed in platelets by enzyme immunometric assay. Subjects were evaluated before and after 6 weeks of lithium treatment at therapeutic levels. Healthy subjects (n = 22) were used as a control group. Results: No differences in phospho-GSK3 beta or total GSK3 beta were observed when comparing drug-free BD subjects in depression and healthy controls. Baseline HAM-D scores were not correlated with phospho GSK3 beta and total GSK3 beta levels. From baseline to endpoint, lithium treatment inactivated GSK3 beta by significantly increasing phospho-GSK3 beta levels (p = 0.010). Clinical improvement (baseline HAM-D endpoint HAM-D) negatively correlated with the increase in phospho-GSK3 beta (p = 0.03). Conclusion: The present results show that lithium inactivates platelet GSK3 beta in BD during mood episodes. No direct association with pathophysiology of BD was observed. Further studies are needed to clarify the role of GSK3 beta as a key biomarker in BD and its association with treatment response as well as the relevance of GSK3 beta in other neuropsychiatric disorders and as a new therapeutic target per se.
- 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, RodrigoSeveral 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.
- 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.