MARCIO GERHARDT SOEIRO DE SOUZA

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LIM/23 - Laboratório de Psicopatologia e Terapêutica Psiquiátrica, Hospital das Clínicas, Faculdade de Medicina

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  • article 39 Citação(ões) na Scopus
    Bcl-2 rs956572 Polymorphism is Associated with Increased Anterior Cingulate Cortical Glutamate in Euthymic Bipolar I Disorder
    (2013) SOEIRO-DE-SOUZA, Marcio Gerhardt; SALVADORE, Giacomo; MORENO, Ricardo Alberto; OTADUY, Maria Concepcion Garcia; CHAIM, Kalil T.; GATTAZ, Wagner F.; ZARATE JR., Carlos A.; MACHADO-VIEIRA, Rodrigo
    B-cell lymphoma 2 (Bcl-2) is an important regulator of cellular plasticity and resilience. In bipolar disorder (BD), studies have shown a key role for a Bcl-2 gene single-nucleotide polymorphism (SNP) rs956572 in the regulation of intracellular calcium (Ca2+) dynamics, Bcl-2 expression/levels, and vulnerability to cellular apoptosis. At the same time, Bcl-2 decreases glutamate (Glu) toxicity in neural cells. Abnormalities in Glu function have been implicated in BD. In magnetic resonance spectroscopy (MRS) studies, anterior cingulated cortex (ACC) Glu levels have been reported to be increased in bipolar depression and mania, but no study specifically evaluated ACC Glu levels in BD-euthymia. Here, we compared ACC Glu levels in BD-euthymia compared with healthy subjects using H-1-MRS and also evaluated the selective role of the rs956572 Bcl-2 SNP in modulating ACC Glu and Glx (sum of Glu and glutamine) in euthymic-BD. Forty euthymic subjects with BD type 1 and forty healthy controls aged 18-40 were evaluated. All participants were genotyped for Bcl-2 rs956572 and underwent a 3-Tesla brain magnetic resonance imaging examination including the acquisition of an in vivo PRESS single voxel (2 cm(3)) H-1-MRS sequence to obtain metabolite levels from the ACC. Euthymic-BD subjects had higher Glu/Cre (creatine) and Glx/Cre compared with healthy controls. The Bcl-2 SNP AA genotype was associated with elevated ACC Glu/Cre and Glx/Cre ratio in the BD group but not in controls. The present study reports for the first time an increase in ACC Glu/Cre and Glx/Cre ratios in BD-euthymia. Also, Bcl-2 AA genotype, previously associated with lower Bcl-2 expression and increase intracellular Ca2+, showed to be associated with increased ACC Glu and Glx levels in euthymic-BD subjects. The present findings reinforce a key role for glutamatergic system dysfunction in the pathophysiology of BD, potentially involving modulatory effects by Bcl-2 in the ACC. Neuropsychopharmacology (2013) 38, 468-475; doi:10.1038/npp.2012.203; published online 17 October 2012
  • article 27 Citação(ões) na Scopus
    Dorsal Anterior Cingulate Lactate and Glutathione Levels in Euthymic Bipolar I Disorder: H-1-MRS Study
    (2016) SOEIRO-DE-SOUZA, Marcio Gerhardt; PASTORELLO, Bruno F.; LEITE, Claudia da Costa; HENNING, Anke; MORENO, Ricardo A.; OTADUY, Maria Concepcion Garcia
    Oxidative stress and mitochondrial dysfunction are 2 closely integrated processes implicated in the physiopathology of bipolar disorder. Advanced proton magnetic resonance spectroscopy techniques enable the measurement of levels of lactate, the main marker of mitochondrial dysfunction, and glutathione, the predominant brain antioxidant. The objective of this study was to measure brain lactate and glutathione levels in bipolar disorder and healthy controls. Eighty-eight individuals (50 bipolar disorder and 38 healthy controls) underwent 3T proton magnetic resonance spectroscopy in the dorsal anterior cingulate cortex (2x2x4.5cm(3)) using a 2-D JPRESS sequence. Lactate and glutathione were quantified using the ProFit software program. Bipolar disorder patients had higher dorsal anterior cingulate cortex lactate levels compared with controls. Glutathione levels did not differ between euthymic bipolar disorder and controls. There was a positive correlation between lactate and glutathione levels specific to bipolar disorder. No influence of medications on metabolites was observed. This is the most extensive magnetic resonance spectroscopy study of lactate and glutathione in bipolar disorder to date, and results indicated that euthymic bipolar disorder patients had higher levels of lactate, which might be an indication of altered mitochondrial function. Moreover, lactate levels correlated with glutathione levels, indicating a compensatory mechanism regardless of bipolar disorder diagnosis.
  • article 6 Citação(ões) na Scopus
    Effects of antidepressant drug therapy with or without physical exercise on inflammatory biomarkers in major depressive disorder: a systematic review and meta-analysis of randomized controlled trials
    (2022) FERNANDES, Beatriz Monteiro; SCOTTI-MUZZI, Estevao; SOEIRO-DE-SOUZA, Marcio Gerhardt
    Objective To conduct a systematic review and meta-analysis of the effects of antidepressant drug therapy (with or without physical exercise) on peripheral inflammatory markers in patients with major depressive disorder (MDD). Methods MEDLINE, PyscINFO, Embase, and Google Scholar databases were searched until May 2020. Randomized trials that measured at least one inflammatory biomarker and included adult outpatients with MDD under antidepressant drug therapy (any drug) with or without physical exercise (any modality) were eligible. Results were summarized using the standardized mean difference (SMD) with 95% confidence intervals (95% CI) under a random-effects model. The Cochrane risk of bias tool (2010) was used to evaluate the risk of bias in the included trials. Results Sixty-three trials were identified, encompassing data from 3482 patients, and 20 investigated biomarkers. Trials had biases across multiple domains, rising concerns primarily to selection bias/performance bias/detection bias/attrition bias. SMDs between pre- and post-results indicated a significant reduction in the levels of IL-2 (SMD, - 0.25; 95% CI, - 0.41 to - 0.09, P = 0.002), IL-6 (SMD, - 0.19; 95% CI, - 0.35 to - 0.025, P = 0.024), IL-10 (SMD, - 0.32; 95% CI, - 0.57 to - 0.07, P = 0.011), and serum cortisol (SMD, - 0.35; 95% CI, - 0.58 to - 0.12, P = 0.002). Evidence supporting the influence of physical exercise combined with antidepressant drugs on peripheral inflammatory markers in MDD is sparse and heterogeneous. Conclusion There is some evidence that antidepressant drug therapy is associated with an overall positive reduction in inflammatory markers, but the evidence is heterogeneous. Further research linking how inflammatory biomarkers modulate physiology related to antidepressant response is required.
  • article 12 Citação(ões) na Scopus
    Lithium-associated anterior cingulate neurometabolic profile in euthymic Bipolar I disorder: A H-1-MRS study
    (2018) SOEIRO-DE-SOUZA, Marcio Gerhardt; OTADUY, Maria Concepcion Garcia; MACHADO-VIEIRA, Rodrigo; MORENO, Ricardo Alberto; NERY, Fabiano G.; LEITE, Claudia; LAFER, Beny
    Objective: In the treatment of Bipolar disorder (BD), achieving euthymia is highly complex and usually requires a combination of mood stabilizers. The mechanism of action in stabilizing mood has not been fully elucidated, but alterations in N-Acetylaspartate (NAA), Myo-Inositol (mI) and Choline (Cho) have been implicated. Proton magnetic resonance spectroscopy (H-1-MRS) is the gold standard technique for measuring brain NAA, Cho and mI in vivo. The objective of this study was to investigate the association of lithium use in BD type I and brain levels of NAA, mI and Cho in the (anterior cingulate cortex) ACC. Methods: 129 BD type I subjects and 79 healthy controls (HC) were submitted to a 3-Tesla brain magnetic resonance imaging scan (H-1-MRS) using a PRESS ACC single voxel (8cm(3)) sequence. Results: BD patients exhibited higher NAA and Cho levels compared to HC. Lithium prescription was associated with lower mI (combination + monotherapy) and higher NAA levels (monotherapy). Conclusion: The results observed add to the knowledge about the mechanisms of action of mood stabilizers on brain metabolites during euthymia. Additionally, the observed decrease in mI levels associated with lithium monotherapy is an in vivo finding that supports the inositol-depletion hypothesis of lithium pharmacodynamics.
  • article 22 Citação(ões) na Scopus
    Anterior cingulate cortex neurometabolites in bipolar disorder are influenced by mood state and medication: A meta-analysis of H-1-MRS studies
    (2021) SCOTTI-MUZZI, Estevao; UMLA-RUNGE, Katja; SOEIRO-DE-SOUZA, Marcio Gerhardt
    The anterior cingulate cortex (ACC), a brain region that mediates affect and cognition by connecting the frontal cortex to limbic structures, has been consistently implicated in the neurobiology of Bipolar Disorder (BD). Proton magnetic resonance spectroscopy (H-1-MRS) studies have extensively compared in vivo neurometabolite levels of BD patients and healthy controls (HC) in the ACC. However, these studies have not been analyzed in a systematic review or meta-analysis and nor has the influence of mood state and medication on neurometabolites been examined in this cortical region. A systematic review and a meta-analysis of H-1-MRS studies comparing ACC neurometabolite profiles of adult BD patients and HC subjects was conducted, retrieving 27 articles published between 2000 and 2018. Overall increased ACC levels of Glx [glutamine (Gln) + glutamate)/Creatine], Gln, choline (Cho) and Cho/Creatine were found in BD compared to HC. Bipolar depression was associated with higher Cho levels, while euthymia correlated with higher glutamine (Gln) and Cho. Mood stabilizers appeared to affect ACC Glu and Gln metabolites. Increased ACC Cho observed in euthymia, depression and in medication-free groups could be considered a trait marker in BD and attributed to increased cell membrane phospholipid turnover. Overall increased ACC Glx was associated with elevated Gln levels, particularly influenced by euthymia, but no abnormality in Glu was detected. Further H-1-MRS studies, on other voxels, should assess more homogeneous (mood state-specific), larger BD samples and account for medication status using more sensitive H-1-MRS techniques.
  • article 17 Citação(ões) na Scopus
    Does BDNF genotype influence creative output in bipolar I manic patients?
    (2012) SOEIRO-DE-SOUZA, Marcio Gerhardt; POST, Robert M.; SOUSA, Mario Lucio de; MISSIO, Giovani; PRADO, Carolina Martins do; GATTAZ, Wagner F.; MORENO, Ricardo A.; MACHADO-VIEIRA, Rodrigo
    Introduction: Creativity is a complex human ability influenced by affective and cognitive components but little is known about its underlying neurobiology. Bipolar Disorder (BD) is highly prevalent among creative individuals. Brain-derived neurotrophic factor (BDNF) is the most widely distributed neurotrophic factor, and has been implicated in the pathophysiology of BD. In contrast to the better functioning of the BDNF polymorphism (Val(66)Met) Val allele, the Met allele decreases BDNF transport and has been associated with worsened performance on several cognitive domains in euthymic BD subjects and controls. We hypothesized that the Val allele is associated with increased creativity in bipolar disorder. Materials and methods: Sixty-six subjects with BD (41 in manic and 25 in depressive episodes) and 78 healthy volunteers were genotyped for BDNF Val(66)Met and tested for creativity using the Barrow Welsh Art Scale (BWAS) and neuropsychological tests. Results: Manic patients with the Val allele (Met-) had higher BWAS scores than Met+ carriers. This relationship was not observed among patients in depressive episodes or among control subjects. BDNF Met allele status showed no association with cognitive function in any of the groups. Conclusion: As postulated, these findings suggest that the better functioning allele of BDNF may selectively facilitate creative thinking in subjects with manic episodes, but not in controls or depressives. Further studies exploring the role of BDNF in the neurobiology of creativity in BD and in euthymic phases are warranted.
  • article 22 Citação(ões) na Scopus
    Creativity and executive function across manic, mixed and depressive episodes in bipolar I disorder
    (2011) SOEIRO-DE-SOUZA, Marcio Gerhardt; DIAS, Vasco Videira; BIO, Danielle Soares; POST, Robert M.; MORENO, Ricardo A.
    Introduction: Creativity is a complex construct involving affective and cognitive components. Bipolar Disorder (BD) has been associated with creativity and is characterized by a wide range of affective and cognitive symptoms. Although studies of creativity in BD have tended to focus on creativity as a trait variable in medicated euthymic patients, it probably fluctuates during symptomatic states of BD. Since creativity is known to involve key affective and cognitive components, it is plausible to speculate that cognitive deficits and symptoms present in symptomatic BD could interfere with creativity. Material and methods: Sixty-seven BD type I patients medication free, age 18-35 years and experiencing a maniac, mixed, or depressive episodes, were assessed for creativity, executive functioning, and intelligence. Results: Manic and mixed state patients had higher creativity scores than depressive individuals. Creativity was influenced by executive function measures only in manic patients. Intelligence did not influence creativity for any of the mood episode types. Conclusion: We propose that creativity in BD might be linked to the putative hyperdopaminergic state of mania and be dependent on intact executive function. Future studies should further explore the role of dopaminergic mechanisms in creativity in BD.
  • article 2 Citação(ões) na Scopus
    Altered brain creatine cycle metabolites in bipolar I disorder with childhood abuse: A H-1 magnetic resonance spectroscopy study
    (2021) BIO, Danielle Soares; MORENO, Ricardo Alberto; GARCIA-OTADUY, Maria Concepcion; NERY, Fabiano; LAFER, Beny; SOEIRO-DE-SOUZA, Marcio Gerhardt
    Background: Childhood abuse (CA) is a risk factor for a number of psychiatric disorders and has been associated with higher risk of developing bipolar disorders (BD). CA in BD has been associated with more severe clinical outcomes, but the neurobiological explanation for this is unknown. Few studies have explored in vivo measurement of brain metabolites using proton magnetic resonance spectroscopy (1H-MRS) in CA and no studies have investigated the association of CA severity with brain neurometabolites in BD. Objective: To investigate whether CA severity is associated with changes in anterior cingulate cortex (ACC) neurometabolite profile in BD and HC subjects. Methods: Fifty-nine BD I euthymic patients and fifty-nine HC subjects were assessed using the Childhood Trauma Questionnaire (CTQ) and underwent a 3-Tesla 1H-MRS scan. Severity of childhood abuse (physical, sexual and emotional) and its association with levels of brain metabolites was analyzed within each group. Results: BD patients had higher total scores on the CTQ and higher severity rates of sexual and physical abuse compared to HC subjects. Greater severity of physical and sexual abuse was associated with increased ACC PCr level and lower Cr/PCr ratio in the BD group only. Conclusion: Sexual and physical abuse in BD patients, but not in HC subjects, appeared to be associated with creatine metabolism in the ACC, which can influence neuronal mitochondrial energy production. Further studies should investigate whether this is the mechanism underlying the association between CA and worse clinical outcomes in BD.
  • article 44 Citação(ões) na Scopus
    Association of the COMT Met(158) allele with trait impulsivity in healthy young adults
    (2013) SOEIRO-DE-SOUZA, Marcio Gerhardt; STANFORD, Matthew S.; BIO, Danielle Soares; MACHADO-VIEIRA, Rodrigo; MORENO, Ricardo Alberto
    Dopamine (DA) is considered to be an important neurotransmitter in the control of impulsive behavior, however, its underlying mechanisms have not been fully elucidated. Catechol-O-methyltransferase (COMT) is a key enzyme in the catabolism of DA within the prefrontal cortex (PFC) and has been suggested to play a role in the mediation of impulsive behavior. The COMT single nucleotide polymorphism (SNP) rs4680 (Val(158)Met) Met allele has been shown to decrease COMT enzyme activity and is associated with improved PFC cognitive function (intelligence and executive functions). Studies have associated the rs4680 genotype with impulsivity as a symptom in attention deficit hyperactivity disorder and substance abuse. However, only a few studies have assessed the effects of rs4680 on impulsiveness in healthy subjects, the results of which remain controversial. The Barratt Impulsiveness Scale (BIS-11) was applied to 82 healthy volunteers (including 42 females) who were genotyped for COMT rs4680. Subjects carrying the Met/Met genotype scored higher for the BIS-11 second-order factor Non-planning than carriers of the Val/Val genotype. No interaction between gender*genotype was detected. Age, gender and education had no effect on the results. The COMT rs4680 Met/Met genotype was associated with higher impulsivity on the BIS-11 second-order factor Non-planning. These results suggest that COMT enzyme activity may be important in the regulation of impulsiveness among young adults. Further studies involving larger samples should be conducted to confirm the results of the present study.
  • article 73 Citação(ões) na Scopus
    Number of manic episodes is associated with elevated DNA oxidation in bipolar I disorder
    (2013) SOEIRO-DE-SOUZA, Marcio Gerhardt; ANDREAZZA, Ana C.; CARVALHO, Andre F.; MACHADO-VIEIRA, Rodrigo; YOUNG, L. Trevor; MORENO, Ricardo Alberto
    Bipolar disorder (BD) is a major public health problem characterized by progressive functional impairment. A number of clinical variables have been associated with progression of the disease, most notably number of affective episodes and presence of psychotic symptoms, both of which correlate with greater cognitive impairment, lower response rates for lithium, and possibly lower levels of neurotrophic factors. Oxidative damage to cytosine and guanosine (8-OHdG) has been described as a modulator of DNA methylation, but the extent of DNA oxidative damage involvement in BD remains unclear. The aim of this study was to evaluate the extent of DNA oxidative damage to 8-OHdG and 5-methylcytosine (5-HMec), as well as global methylation (5-Mec), in BD patients and healthy controls. Potential association with clinical variables was also investigated. DNA levels of 8-OHdG, 5-HMec and 5-Mec were measured in 50 BD type I patients and 50 healthy controls. DNA 8-OHdG levels were higher in BD patients compared to healthy controls and found to be positively influenced by number of previous manic episodes. BD subjects had lower levels of 5-HMec compared to controls, whereas this measure was not influenced by the clinical features of BD. Number of manic episodes was correlated with higher levels of 8-OHdG, but not of 5-Mec or 5-HMec. Lower demethylation activity (5-HMec) but no difference in global 5-Mec levels was observed in BD. This finding suggests that oxidative damage to 8-OHdG might be a potential marker of disease progression, although further prospective cross-sectional studies to confirm neuroprogression in BD are warranted.