LEANDRO DA COSTA LANE VALIENGO
Projetos de Pesquisa
Unidades Organizacionais
Instituto de Psiquiatria, Hospital das Clínicas, Faculdade de Medicina - Médico
LIM/27 - Laboratório de Neurociências, Hospital das Clínicas, Faculdade de Medicina
LIM/27 - Laboratório de Neurociências, Hospital das Clínicas, Faculdade de Medicina
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- Impact of 5-HTTLPR and BDNF polymorphisms on response to sertraline versus transcranial direct current stimulation: Implications for the serotonergic system(2013) BRUNONI, A. R.; KEMP, A. H.; SHIOZAWA, P.; CORDEIRO, Q.; VALIENGO, L. C. L.; GOULART, A. C.; COPRERSKI, B.; LOTUFO, P. A.; BRUNONI, D.; PEREZ, A. B. A.; FREGNI, F.; BENSENOR, I. M.Transcranial direct current stimulation (tDCS) has been intensively investigated as a non-pharmacological treatment for major depressive disorder (MDD). While many studies have examined the genetic predictors of antidepressant medications, this issue remains to be investigated for tDCS. In the current study, we evaluated whether the BDNF Val66Met and the 5-HTT (5-HTTLPR) polymorphisms were associated with tDCS antidepressant response. We used data from a factorial trial that evaluated the efficacy of tDCS and sertraline and enrolled 120 moderate-to-severe, antidepressant-free participants. In the present study, we used analyses of variance to evaluate whether the BDNF (Val/Val vs. Met-carries) and 5-HTTLPR alleles (long/long vs short-carriers) were predictors of tDCS (active/sham) and sertraline (sertraline/placebo) response. Analyses were conducted on the polymorphisms separately and also on their interaction. Genotype frequencies were in Hardy-Weinberg equilibrium. BDNF polymorphism was not associated with treatment response. We found that 5-HTTLPR predicted tDCS effects as long/long homozygotes displayed a larger improvement comparing active vs. sham tDCS, while short-allele carriers did not. A dose-response relationship between active-sham differences with the long allele was also suggested. These results strengthen the role of the serotonergic system in the tDCS antidepressant effects and expand previous findings that reported that tDCS mechanisms of action partially involve serotonergic receptors. Therefore, we hypothesize that tDCS is a neuromodulation technique that acts over depression through the modulation of serotonergic system and that tDCS ""top-down"" antidepressant effects might not be optimal in brain networks with a hyperactive amygdala inducing bottom-up effects, such as occurs in short-carriers.
- Formal Thought Disorder and language impairment in schizophrenia(2013) RADANOVIC, Marcia; SOUSA, Rafael T. de; VALIENGO, Leandro L.; GATTAZ, Wagner Farid; FORLENZA, Orestes VicenteSchizophrenia is a psychiatric illness in which disorders of thought content are a prominent feature. The disruption of normal flow of thought, or ""Formal Thought Disorder"" (FTD), has been traditionally assessed through the content and form of patients' speech, and speech abnormalities in schizophrenia were considered as a by-product of the disruption in conceptual structures and associative processes related to psychosis. This view has been changed due to increasing evidence that language per se is impaired in schizophrenia, especially its semantic, discursive, and pragmatic aspects. Schizophrenia is currently considered by some authors as a ""language related human specific disease"" or ""logopathy"", and the neuroanatomical and genetic correlates of the language impairment in these patients are under investigation. Such efforts may lead to a better understanding about the pathophysiology of this devastating mental disease. We present some current concepts related to FTD as opposed to primary neurolinguistic abnormalities in schizophrenia.
- THE SERTRALINE VERSUS ELECTRICAL CURRENT THERAPY FOR TREATING DEPRESSION CLINICAL STUDY (SELECT-TDCS): RESULTS OF THE CROSSOVER AND FOLLOW-UP PHASES(2013) VALIENGO, Leandro; BENSENOR, Isabela Martins; GOULART, Alessandra C.; OLIVEIRA, Janaina Farias de; ZANAO, Tamires Araujo; BOGGIO, Paulo Sergio; LOTUFO, Paulo Andrade; FREGNI, Felipe; BRUNONI, Andre RussowskyBackgroundTranscranial direct current stimulation (tDCS) is a promising nonpharmacological therapy for major depression. In the Sertraline versus Electrical Current Therapy for Treating Depression Clinical Trial (SELECT-TDCS) trial, phase-I (Brunoni et al., JAMA Psychiatry, 2013) we found that tDCS is effective for the acute episode. Here, we describe tDCS effects during phases II (crossover) and III (follow-up) of this trial (NCTs: 01149889 and 01149213). MethodsPhase II (n = 25) was the open-label, crossover phase in which phase-I nonresponders who had received sham-tDCS received a 10-day course of active-tDCS. In phase-III (n = 42), all active-tDCS responders (>50% Montgomery-Asberg Depression Rating Scale (MADRS) improvement or MADRS 12) were enrolled to a 24-week, follow-up phase in which a maximum of nine tDCS sessions were performedevery other week for 3 months and, thereafter, once a month for the subsequent 3 monthssessions would be interrupted earlier whether the subject relapsed. TDCS was applied at 2 mA/30 min, with the anode over the left and the cathode over the right dorsolateral prefrontal cortex. Relapse was the outcome measure. ResultsIn phase-II, 52% of completers responded to tDCS. In phase-III, the mean response duration was 11.7 weeks. The survival rate per Kaplan-Meier analysis was 47%. Patients with treatment-resistant depression presented a much lower 24-week survival rate as compared to nonrefractory patients (10% vs. 77%, OR = 5.52; P < .01). Antidepressant use (sertraline 50 mg/day, eight patients) was not a predictor of relapse. TDCS was well tolerated and with few side effects. ConclusionContinuation tDCS protocols should be optimized as to prevent relapse among tDCS responders, particularly for patients with baseline treatment-resistant depression. Depression and Anxiety 30: 646-653, 2013. (C) 2013 Wiley Periodicals, Inc.
- Acute working memory improvement after tDCS in antidepressant-free patients with major depressive disorder(2013) OLIVEIRA, Janaina F.; ZANAO, Tamires A.; VALIENGO, Leandro; LOTUFO, Paulo A.; BENSENOR, Isabela M.; FREGNI, Felipe; BRUNONI, Andre R.Based on previous studies showing that transcranial direct current stimulation (tDCS), a non-invasive brain stimulation technique that employs weak, direct currents to induce cortical-excitability changes, might be useful for working memory (WM) enhancement in healthy subjects and also in treating depressive symptoms, our aim was to evaluate whether tDCS could acutely enhance WM in depressed patients. Twenty-eight age- and gender-matched, antidepressant-free depressed subjects received a single-session of active/sham tDCS in a randomized, double-blind, parallel design. The anode was positioned over the left and the cathode over the right dorsolateral prefrontal cortex. The n-back task was used for assessing WM and it was performed immediately before and 15 min after tDCS onset. We found that active vs. sham tDCS led to an increase in the rate of correct responses. We also used signal detection theory analyses to show that active tDCS increased both discriminability, i.e., the ability to discriminate signal (correct responses) from noise (false alarms), and response criterion, indicating a lower threshold to yield responses. All effect sizes were large. In other words, one session of tDCS acutely enhanced WM in depressed subjects, suggesting that tDCS can improve ""cold"" (non affective-loaded) working memory processes in MDD. Based on these findings, we discuss the effects of tDCS on WM enhancement in depression. We also suggest that the n-back task could be used as a biomarker in future tDCS studies investigating prefrontal activity in healthy and depressed samples.
- The Sertraline vs Electrical Current Therapy for Treating Depression Clinical Study Results From a Factorial, Randomized, Controlled Trial(2013) BRUNONI, Andre R.; VALIENGO, Leandro; BACCARO, Alessandra; ZANAO, Tamires A.; OLIVEIRA, Janaina F. de; GOULART, Alessandra; BOGGIO, Paulo S.; LOTUFO, Paulo A.; BENSENOR, Isabela M.; FREGNI, FelipeImportance: Transcranial direct current stimulation (tDCS) trials for major depressive disorder (MDD) have shown positive but mixed results. Objective: To assess the combined safety and efficacy of tDCS vs a common pharmacological treatment (sertraline hydrochloride, 50 mg/d). Design: Double-blind, controlled trial. Participants were randomized using a 2 x 2 factorial design to sertraline/placebo and active/sham tDCS. Setting: Outpatient, single-center academic setting in Sao Paulo, Brazil. Participants: One hundred twenty antidepressant free patients with moderate to severe, nonpsychotic, unipolar MDD. Interventions: Six-week treatment of 2-mA anodal left/cathodal right prefrontal tDCS (twelve 30-minute sessions: 10 consecutive sessions once daily from Monday to Friday plus 2 extra sessions every other week) and sertraline hydrochloride (50 mg/d). Main Outcome Measures: In this intention-to-treat analysis, the primary outcome measure was the change in Montgomery-Asberg Depression Rating Scale score at 6 weeks (end point). We considered a difference of at least 3 points to be clinically relevant. The analysis plan was previously published. Safety was measured with an adverse effects questionnaire, the Young Mania Rating Scale, and cognitive assessment. Secondary measures were rates of clinical response and remission and scores on other scales. Results: At the main end point, there was a significant difference in Montgomery-Asberg Depression Rating Scale scores when comparing the combined treatment group (sertraline/active tDCS) vs sertraline only (mean difference, 8.5 points; 95% CI, 2.96 to 14.03; P = .002), tDCS only (mean difference, 5.9 points; 95% CI, 0.36 to 11.43; P = .03), and placebo/sham tDCS (mean difference, 11.5 points; 95% CI, 6.03 to 17.10; P < .001). Analysis of tDCS only vs sertraline only presented comparable efficacies (mean difference, 2.6 points; 95% CI, -2.90 to 8.13; P = .35). Use of tDCS only (but not sertraline only) was superior to placebo/sham tDCS. Common adverse effects did not differ between interventions, except for skin redness on the scalp in active tDCS (P = .03). There were 7 episodes of treatment-emergent mania or hypomania, 5 occurring in the combined treatment group. Conclusions and Relevance: In MDD, the combination of tDCS and sertraline increases the efficacy of each treatment. The efficacy and safety of tDCS and sertraline did not differ.
- Bifrontal tDCS prevents implicit learning acquisition in antidepressant-free patients with major depressive disorder(2013) BRUNONI, Andre Russowsky; ZANAO, Tamires Araujo; FERRUCCI, Roberta; PRIORI, Alberto; VALIENGO, Leandro; OLIVEIRA, Janaina Farias de; BOGGIO, Paulo S.; LOTUFO, Paulo A.; BENSENOR, Isabela M.; FREGNI, FelipeThe findings for implicit (procedural) learning impairment in major depression are mixed. We investigated this issue using transcranial direct current stimulation (tDCS), a method that non-invasively increases/decreases cortical activity. Twenty-eight age- and gender-matched, antidepressant-free depressed subjects received a single-session of active/sham tDCS. We used a bifrontal setup - anode and cathode over the left and the right dorsolateral prefrontal cortex (DLPFC), respectively. The probabilistic classification-learning (PCL) task was administered before and during tDCS. The percentage of correct responses improved during sham; although not during active tDCS. Procedural or implicit learning acquisition between tasks also occurred only for sham. We discuss whether DLPFC activation decreased activity in subcortical structures due to the depressive state, The deactivation of the right DLPFC by cathodal tDCS can also account for our results. To conclude, active bifrontal tDCS prevented implicit learning in depressive patients. Further studies with different tDCS montages and in other samples are necessary.
- Transcranial direct current stimulation and repetitive transcranial magneticstimulation in consultation-liaison psychiatry(2013) VALIENGO, L. C. L.; BENSENOR, I. M.; LOTUFO, P. A.; FRAGUAS JR., R.; BRUNONI, A. R.Patients with clinical diseases often present psychiatric conditions whose pharmacological treatment is hampered due to hazardous interactions with the clinical treatment and/or disease. This is particularly relevant for major depressive disorder, the most common psychiatric disorder in the general hospital. In this context, nonpharmacological interventions could be useful therapies; and, among those, noninvasive brain stimulation (NIBS) might be an interesting option. The main methods of NIBS are repetitive transcranial magnetic stimulation (rTMS), which was recently approved as a nonresearch treatment for some psychiatric conditions, and transcranial direct current stimulation (tDCS), a technique that is currently limited to research scenarios but has shown promising results. Therefore, our aim was to review the main medical conditions associated with high depression rates, the main obstacles for depression treatment, and whether these therapies could be a useful intervention for such conditions. We found that depression is an important and prevalent comorbidity in a variety of diseases such as epilepsy, stroke, Parkinson's disease, myocardial infarction, cancer, and in other conditions such as pregnancy and in patients without enteral access. We found that treatment of depression is often suboptimal within the above contexts and that rTMS and tDCS therapies have been insufficiently appraised. We discuss whether rTMS and tDCS could have a significant impact in treating depression that develops within a clinical context, considering its unique characteristics such as the absence of pharmacological interactions, the use of a nonenteral route, and as an augmentation therapy for antidepressants.
conferenceObject Epistasis Between COMT Val(158)Met and DRD3 SER(9)Gly Polymorphisms on Cognitive Function of Individuals with Schizophrenia(2013) 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.Background: The present study aimed to determine the influence of cathecol-O-methyl-transferase(COMT) Val158Met and dopamine receptor D3 (DRD3) Ser9Gly polymorphisms on cognitive functioning of individuals with schizophrenia and controls. Methods: Fifty-eight outpatients with schizophrenia from the Institute of Psychiatry, Sao Paulo, and 89 controls from the same geographical area with no psychiatric or neurological disorders were recruited. Neurocognitive battery assessed: attention, verbal memory, visual memory, visuospatial function, language, psychomotor speed, executive function, intelligence. DNA was extracted from peripheral blood and genotyped for COMT Val158Met and DRD3 Ser9Gly; real-time PCR allelic discrimination with TaqMan®SNP Genotyping Assays was used. Analyses of variance (ANOVAs) controlling for sex, age and years of education were used to compare neuropsychological performance between both genotypes in controls and in patients. Results: Worst executive function was observed for DRD3 Ser/Gly carriers in controls (r=0.07,p=0.04); no DRD3 genotype effect was seen in patients. Regarding COMT, Val/Val patients had significantly worse attention (r=0.12,p=0.02); for Met/Met both patients (r=0.15,p=0.02) and controls (r=0.10,p=0.01) showed worse executive functioning. For the interaction of COMT and DRD3 polymorphisms, genotypes had significant effect among executive function in controls and patients (ES=0.137,p=0.006); all controls had similar scores. COMT Val/Val patients also performed equally to controls. As COMT Met allele frequency increased, cognitive functioning worsened in patients; this effect was maximum when combined with DRD3 Ser/Ser. Conclusions: Results support the influence of combined genetic polymorphisms related to dopamine in cognitive functioning in schizophrenia. More studies considering epistatic effects of multiple polymorphisms should be conducted to assess candidate endophenotypes.