Cognitive outcomes of the bipolar depression electrical treatment trial (BETTER): a randomized, double-blind, sham-controlled study.

Bipolar depression is associated with marked cognitive deficits. Pharmacological treatments for this condition are limited and may aggravate depressive and cognitive symptoms. Therefore, therapeutic interventions that preserve adequate cognitive functioning are necessary. Our previous results demonstrated significant clinical efficacy of transcranial direct current stimulation (tDCS) in the Bipolar Depression Electrical Treatment Trial (BETTER). Here, cognitive outcomes of this study are reported. We randomized 59 patients with bipolar disorder I or II in an acute depressive episode to receive active (12 2 mA, 30-min, anodal-left, cathodal-right prefrontal cortex tDCS sessions) or sham tDCS. Patients were on stable pharmacological regimen for at least 2 weeks. A battery of 12 neuropsychological assessments in five cognitive domains (attention and processing speed, memory, language, inhibitory control, and working memory and executive function) was performed at baseline, after two weeks and at endpoint (week 6). No significant differences between groups over 6 weeks of treatment were observed for any cognitive outcomes. Moreover, no decrease in cognitive performance was observed. Our findings warrant further replication in larger studies. Trial Registration: clinicaltrials.gov Identifier: NCT02152878.

Trial of Electrical Direct-Current Therapy versus Escitalopram for Depression.

BACKGROUND: We compared transcranial direct-current stimulation (tDCS) with a selective serotonin-reuptake inhibitor for the treatment of depression. METHODS: In a single-center, double-blind, noninferiority trial involving adults with unipolar depression, we randomly assigned patients to receive tDCS plus oral placebo, sham tDCS plus escitalopram, or sham tDCS plus oral placebo. The tDCS was administered in 30-minute, 2-mA prefrontal stimulation sessions for 15 consecutive weekdays, followed by 7 weekly treatments. Escitalopram was given at a dose of 10 mg per day for 3 weeks and 20 mg per day thereafter. The primary outcome measure was the change in the 17-item Hamilton Depression Rating Scale (HDRS-17) score (range, 0 to 52, with higher scores indicating more depression). Noninferiority of tDCS versus escitalopram was defined by a lower boundary of the confidence interval for the difference in the decreased score that was at least 50% of the difference in the scores with placebo versus escitalopram. RESULTS: A total of 245 patients underwent randomization, with 91 being assigned to escitalopram, 94 to tDCS, and 60 to placebo. In the intention-to-treat analysis, the mean (±SD) decrease in the score from baseline was 11.3±6.5 points in the escitalopram group, 9.0±7.1 points in the tDCS group, and 5.8±7.9 points in the placebo group. The lower boundary of the confidence interval for the difference in the decrease for tDCS versus escitalopram (difference, -2.3 points; 95% confidence interval [CI], -4.3 to -0.4; P=0.69) was lower than the noninferiority margin of -2.75 (50% of placebo minus escitalopram), so noninferiority could not be claimed. Escitalopram and tDCS were both superior to placebo (difference vs. placebo, 5.5 points [95% CI, 3.1 to 7.8; P<0.001] and 3.2 points [95% CI, 0.7 to 5.5; P=0.01], respectively). Patients receiving tDCS had higher rates of skin redness, tinnitus, and nervousness than did those in the other two groups, and new-onset mania developed in 2 patients in the tDCS group. Patients receiving escitalopram had more frequent sleepiness and obstipation than did those in the other two groups. CONCLUSIONS: In a single-center trial, tDCS for the treatment of depression did not show noninferiority to escitalopram over a 10-week period and was associated with more adverse events. (Funded by Fundação de Amparo à Pesquisa do Estado de São Paulo and others; ELECT-TDCS ClinicalTrials.gov number, NCT01894815 .).

Transcranial direct current stimulation (tDCS) for preventing major depressive disorder relapse: Results of a 6-month follow-up.

BACKGROUND: The efficacy of transcranial direct current stimulation (tDCS) as a continuation therapy for the maintenance phase of the depressive episode is low and insufficiently investigated in literature. We investigated whether it could be enhanced by using a more intensive treatment regimen compared to previous reports. METHODS: Twenty-four patients (16 with unipolar depression and eight with bipolar depression) who presented acute tDCS response (≥50% depression improvement in the Hamilton Depression Rating Scale [HDRS]) after receiving 15 tDCS sessions were followed for up to 6 months or until relapse, defined as clinical worsening and/or HDRS > 15. Sessions were performed twice a week (maximum of 48 sessions) over 24 weeks. The anode and the cathode were positioned over the left and right dorsolateral prefrontal cortex (2 mA current, 30 min sessions were delivered). We performed Kaplan-Meier survival analysis and Cox proportional hazards ratios to evaluate predictors of relapse. RESULTS: Out of 24 patients, 18 completed the follow-up period. tDCS treatment was well tolerated. The mean survival duration was 17.5 weeks (122 days). The survival rate at the end of follow-up was 73.5% (95% confidence interval, 50-87). A trend (P = 0.09) was observed for lower relapse rates in nontreatment- vs. antidepressant treatment-resistant patients (7.7% vs. 45.5%, respectively). No differences in efficacy between unipolar and bipolar depression were observed. CONCLUSION: An intensive tDCS treatment regimen consisting of sessions twice a week achieved relatively low relapse rates after a 6-month follow up of tDCS responders, particularly for nontreatment-resistant patients.

The Influence of Skin Redness on Blinding in Transcranial Direct Current Stimulation Studies: A Crossover Trial.

OBJECTIVE: To evaluate whether and to which extent skin redness (erythema) affects investigator blinding in transcranial direct current stimulation (tDCS) trials. MATERIAL AND METHODS: Twenty-six volunteers received sham and active tDCS, which was applied with saline-soaked sponges of different thicknesses. High-resolution skin images, taken before and 5, 15, and 30 min after stimulation, were randomized and presented to experienced raters who evaluated erythema intensity and judged on the likelihood of stimulation condition (sham vs. active). In addition, semi-automated image processing generated probability heatmaps and surface area coverage of erythema. Adverse events were also collected. RESULTS: Erythema was present, but less intense in sham compared to active groups. Erythema intensity was inversely and directly associated to correct sham and active stimulation group allocation, respectively. Our image analyses found that erythema also occurs after sham and its distribution is homogenous below electrodes. Tingling frequency was higher using thin compared to thick sponges, whereas erythema was more intense under thick sponges. CONCLUSIONS: Optimal investigator blinding is achieved when erythema after tDCS is mild. Erythema distribution under the electrode is patchy, occurs after sham tDCS and varies according to sponge thickness. We discuss methods to address skin erythema-related tDCS unblinding.

Prevalence and correlates of cannabis use among athletes-A systematic review.

BACKGROUND AND OBJECTIVES: Despite scientific evidence that marijuana impairs performance and mental health, there is evidence that some athletes are at higher risk for use. This review aims to identify possible risk factors associated with marijuana use in athletes. METHODS: A search was conducted in the PubMed database with the keywords: (marijuana OR cannabis OR tetrahydrocannabinol OR delta-9-tetrahydrocannabinol OR THC) AND (sports OR sport OR athlete OR athletes). We retrieved 186 studies. After applying the inclusion/exclusion criteria, 15 studies remained for review. RESULTS: The review revealed a number of potential risk factors for marijuana use among adult athletes, including being male, Caucasian, using sport performance-enhancing drugs, using marijuana to enhance recreation or non-sport performance, and practicing specific types of sports including skeleton, bobsleding, and ice hockey. Contrary to use patterns in the general population, among athletes marijuana appears to take the place of tobacco as the second most widely used drug, after alcohol. Many elite athletes denied the use of marijuana, which suggests that toxicological testing is an important tool for identifying users, because it is more accurate than self-report. Geography appears important, as in areas of high consumption, prevalence among athletes appears to be greater as well. CONCLUSION AND SCIENTIFIC SIGNIFICANCE: Contrary to the image that athletes do not use psychoactive drugs, this review suggests that a number of athletic subgroups are at increased risk for marijuana use. Surprisingly, a common rationale for use appears to be to enhance sports performance. As in the general population, experimentation starts early-in pre-adolescence-at an age that prevention and guidance programs could have positive influences. (Am J Addict 2016;25:518-528).

Effects of tDCS on neuroplasticity and inflammatory biomarkers in bipolar depression: Results from a sham-controlled study.

OBJECTIVES: We investigated the role of peripheral biomarkers associated with neuroplasticity and immune-inflammatory processes on the effects of transcranial direct current stimulation (tDCS), a safe, affordable, and portable non-invasive neuromodulatory treatment, in bipolar depression. METHODS: This is an exploratory analysis using a dataset from the sham-controlled study the Bipolar Depression Electrical Treatment Trial (BETTER)(clinicaltrials.govNCT02152878). Participants were 52 adults with type I or II bipolar disorder in a moderate-to-severe depressive episode, randomized to 12 bifrontal active or sham tDCS sessions over a 6-week treatment course. Plasma levels of brain derived neurotrophic factor (BDNF), glial cell derived neurotrophic factor (GDNF), interleukins (IL) 2, 4, 6, 8, 10, 18, 33, 1ß, 12p70, 17a, interferon gamma (IFN), tumor necrosis factor alpha (TNF) and its soluble receptors 1 and 2, ST2, and KLOTHO were investigated at baseline and endpoint. We performed analyses unadjusted for multiple testing to evaluate whether baseline biomarkers were predictive for depression improvement and changed during treatment using linear regression models. RESULTS: A time x group interaction (Cohen's d: -1.16, 95% CI = -1.96 to -0.3, p = .005) was found for IL-8, with greater reductions after active tDCS. Higher baseline IL-6 plasma levels was associated with symptomatic improvement after tDCS (F(1,43) = 5.43; p = .025). Other associations were not significant. CONCLUSIONS: Our exploratory findings suggested that IL-6 is a potential predictor of tDCS response and IL-8 might decrease after tDCS; although confirmatory studies are warranted due to the multiplicity of comparisons.

Noninvasive brain stimulation in psychiatric disorders: a primer.

OBJECTIVE: Noninvasive brain stimulation (NIBS) techniques, such as transcranial direct current stimulation (tDCS) and repetitive transcranial magnetic stimulation (rTMS), are increasingly being used to treat mental disorders, particularly major depression. The aim of this comprehensive review is to summarize the main advances, limitations, and perspectives of the field. METHODS: We searched PubMed and other databases from inception to July 2017 for articles, particularly systematic reviews and meta-analyses, evaluating the use of NIBS in psychiatric disorders. RESULTS: We reviewed the mechanisms of action, safety, tolerability, efficacy, and relevant clinical parameters of NIBS. Repetitive TMS is already an established technique for the treatment of depression, and there is theoretically room for further methodological development towards a high-end therapeutic intervention. In contrast, tDCS is a technically easier method and therefore potentially suitable for wider clinical use. However the evidence of its antidepressant efficacy is less sound, and a recent study found tDCS to be inferior to antidepressant pharmacotherapy. Clinical trials using rTMS for other mental disorders produced mixed findings, whereas tDCS use has not been sufficiently appraised. CONCLUSION: The most promising results of NIBS have been obtained for depression. These techniques excel in safety and tolerability, although their efficacy still warrants improvement.

Associations between symptoms of depression and heart rate variability: An exploratory study.

Major depressive disorder (MDD) is associated with decreased heart rate variability (HRV), a predictor of cardiovascular morbidity by many, but not all studies. This inconsistency could be due to the association of HRV with specific depressive symptoms. Here, we investigated the association of HRV parameters with components of depressive symptoms from 120 MDD patients, at baseline of a published trial comparing the effect of sertraline to transcranial direct current stimulation. We used Principal Component Analysis to extract components of the Hamilton Rating Scale for Depression (HAM-D-17), the Montgomery Asberg Depression Rating Scale (MADRS) and the Beck Inventory for Depressive Symptomatology (BDI). We constructed one equation of multiple linear regression for each HRV parameter as the dependent variable, and the components of depressive symptoms of the three scales as the independent ones, adjusted for age and gender. A component of HAM-D-17 predicted LF/HF (low frequency/high frequency) and a component of MADRS predicted LF (low frequency). "Guilt" and "loss of interest/pleasure in activities" were present in the components of both scales, and the MADRS component also included "psychomotor retardation". These results suggest that melancholic features might be relevant for the association between MDD and HRV. Considering multiple comparisons, these results are preliminary.

Efficacy and Safety of Transcranial Direct Current Stimulation as an Add-on Treatment for Bipolar Depression: A Randomized Clinical Trial.

Importance: More effective, tolerable interventions for bipolar depression treatment are needed. Transcranial direct current stimulation (tDCS) is a novel therapeutic modality with few severe adverse events that showed promising results for unipolar depression. Objective: To determine the efficacy and safety of tDCS as an add-on treatment for bipolar depression. Design, Setting, and Participants: A randomized, sham-controlled, double-blind trial (the Bipolar Depression Electrical Treatment Trial [BETTER]) was conducted from July 1, 2014, to March 30, 2016, at an outpatient, single-center academic setting. Participants included 59 adults with type I or II bipolar disorder in a major depressive episode and receiving a stable pharmacologic regimen with 17-item Hamilton Depression Rating Scale (HDRS-17) scores higher than 17. Data were analyzed in the intention-to-treat sample. Interventions: Ten daily 30-minute, 2-mA, anodal-left and cathodal-right prefrontal sessions of active or sham tDCS on weekdays and then 1 session every fortnight until week 6. Main Outcomes and Measures: Change in HDRS-17 scores at week 6. Results: Fifty-nine patients (40 [68%] women), with a mean (SD) age of 45.9 (12) years participated; 36 (61%) with bipolar I and 23 (39%) with bipolar II disorder were randomized and 52 finished the trial. In the intention-to-treat analysis, patients in the active tDCS condition showed significantly superior improvement compared with those receiving sham (ßint = -1.68; number needed to treat, 5.8; 95% CI, 3.3-25.8; P = .01). Cumulative response rates were higher in the active vs sham groups (67.6% vs 30.4%; number needed to treat, 2.69; 95% CI, 1.84-4.99; P = .01), but not remission rates (37.4% vs 19.1%; number needed to treat, 5.46; 95% CI, 3.38-14.2; P = .18). Adverse events, including treatment-emergent affective switches, were similar between groups, except for localized skin redness that was higher in the active group (54% vs 19%; P = .01). Conclusions and Relevance: In this trial, tDCS was an effective, safe, and tolerable add-on intervention for this small bipolar depression sample. Further trials should examine tDCS efficacy in a larger sample. Trial Registration: clinicaltrials.gov Identifier: NCT02152878.

Treatment-emergent mania/hypomania during antidepressant treatment with transcranial direct current stimulation (tDCS): A systematic review and meta-analysis.

BACKGROUND: Treatment-emergent mania/hypomania (TEM) is a possible adverse effect of pharmacological and non-pharmacological antidepressant treatments. OBJECTIVE: We performed a systematic review and meta-analysis to evaluate the risk of TEM in depressed patients during randomized, sham-controlled trials (RCTs). DATA SOURCES: Medline database, from the first date available to August 12, 2016. RESULTS: From 283 references, 10 RCTs were identified. Only 3 of them described TEM. In active and sham groups, respectively, only 8 of 226 (3.5%) and 1 of 190 (0.5%) participants presented TEM. This difference was not statistically significant (OR = 1.79, 95% CI = 0.6 to 5.32). There were also five additional reports of TEM in participants not on RCTs. No risk factors for TEM were identified. LIMITATIONS: Low number of studies and TEM reports. CONCLUSION: Despite previous reports, active vs. sham tDCS was not associated with a significantly greater number of TEM episodes.

Treatment of Bipolar Depression with Deep TMS: Results from a Double-Blind, Randomized, Parallel Group, Sham-Controlled Clinical Trial.

Bipolar depression (BD) is a highly prevalent condition with limited therapeutic options. Deep (H1-coil) transcranial magnetic stimulation (dTMS) is a novel TMS modality with established efficacy for unipolar depression. We conducted a randomized sham-controlled trial to evaluate the efficacy and safety of dTMS in treatment-resistant BD patients. Patients received 20 sessions of active or sham dTMS over the left dorsolateral prefrontal cortex (H1-coil, 55 18 Hz 2 s 120% MT trains). The primary outcome was changes in the 17-item Hamilton Depression Rating Scale (HDRS-17) from baseline to endpoint (week 4). Secondary outcomes were changes from baseline to the end of the follow-up phase (week 8), and response and remission rates. Safety was assessed using a dTMS adverse effects questionnaire and the Young Mania Rating Scale to assess treatment-emergent mania switch (TEMS). Out of 50 patients, 43 finished the trial. There were 2 and 5 dropouts in the sham and active groups, respectively. Active dTMS was superior to sham at end point (difference favoring dTMS=4.88; 95% CI 0.43 to 9.32, p=0.03) but not at follow-up. There was also a trend for greater response rates in the active (48%) vs sham (24%) groups (OR=2.92; 95% CI=0.87 to 9.78, p=0.08). Remission rates were not statistically different. No TEMS episodes were observed. Deep TMS is a potentially effective and well-tolerated add-on therapy in resistant bipolar depressed patients receiving adequate pharmacotherapy.

Plasma levels of soluble TNF receptors 1 and 2 after tDCS and sertraline treatment in major depression: Results from the SELECT-TDCS trial.

BACKGROUND: The cytokine hypothesis of depression postulates that the pathophysiology of this illness incorporates an increased production of pro-inflammatory cytokines, which leads to an over-activation of the hypothalamic-pituitary-adrenal axis as well as monoaminergic disturbances. Nevertheless, it remains unclear whether the amelioration of depressive symptoms could decrease cytokine levels. Notwithstanding antidepressant drug therapy might exert anti-inflammatory effects, the effects of non-invasive neuromodulatory approaches like transcranial direct current stimulation (tDCS) on pro-inflammatory cytokine networks are largely unknown. METHODS: We evaluated, in the Sertraline vs. Electric Current Therapy for Treating Depression Clinical Study (SELECT-TDCS) trial, whether the plasma levels of the soluble TNF receptors 1 and 2 (sTNFRs) changed after antidepressant treatment in a sample of 73 antidepressant-free patients with unipolar depressive disorder in an episode of at least moderate intensity. RESULTS: Although both tDCS and sertraline exerted antidepressant effects, the plasma levels of sTNFRs did not change over time regardless of the intervention and clinical response. Also, baseline sTNFRs levels did not predict antidepressant response. LIMITATIONS: Our negative findings could be a type II error, as this trial did not use an equivalence design. CONCLUSIONS: To conclude, in this novel placebo-controlled trial prospectively evaluating the changes of sTNFRs in depressed patients, we found that these molecules are not surrogate biomarkers of treatment response of tDCS, whose antidepressant effects occurred regardless of normalization of immunological activity.

The Escitalopram versus Electric Current Therapy for Treating Depression Clinical Study (ELECT-TDCS): rationale and study design of a non-inferiority, triple-arm, placebo-controlled clinical trial.

CONTEXT AND OBJECTIVE: Major depressive disorder (MDD) is a common psychiatric condition, mostly treated with antidepressant drugs, which are limited due to refractoriness and adverse effects. We describe the study rationale and design of ELECT-TDCS (Escitalopram versus Electric Current Therapy for Treating Depression Clinical Study), which is investigating a non-pharmacological treatment known as transcranial direct current stimulation (tDCS). DESIGN AND SETTING: Phase-III, randomized, non-inferiority, triple-arm, placebo-controlled study, ongoing in São Paulo, Brazil. METHODS: ELECT-TDCS compares the efficacy of active tDCS/placebo pill, sham tDCS/escitalopram 20 mg/day and sham tDCS/placebo pill, for ten weeks, randomizing 240 patients in a 3:3:2 ratio, respectively. Our primary aim is to show that tDCS is not inferior to escitalopram with a non-inferiority margin of at least 50% of the escitalopram effect, in relation to placebo. As secondary aims, we investigate several biomarkers such as genetic polymorphisms, neurotrophin serum markers, motor cortical excitability, heart rate variability and neuroimaging. RESULTS: Proving that tDCS is similarly effective to antidepressants would have a tremendous impact on clinical psychiatry, since tDCS is virtually devoid of adverse effects. Its ease of use, portability and low price are further compelling characteristics for its use in primary and secondary healthcare. Multimodal investigation of biomarkers will also contribute towards understanding the antidepressant mechanisms of action of tDCS. CONCLUSION: Our results have the potential to introduce a novel technique to the therapeutic arsenal of treatments for depression.

Noninvasive brain stimulation in psychiatric disorders: a primer

Objective: Noninvasive brain stimulation (NIBS) techniques, such as transcranial direct current stimulation (tDCS) and repetitive transcranial magnetic stimulation (rTMS), are increasingly being used to treat mental disorders, particularly major depression. The aim of this comprehensive review is to summarize the main advances, limitations, and perspectives of the field. Methods: We searched PubMed and other databases from inception to July 2017 for articles, particularly systematic reviews and meta-analyses, evaluating the use of NIBS in psychiatric disorders. Results: We reviewed the mechanisms of action, safety, tolerability, efficacy, and relevant clinical parameters of NIBS. Repetitive TMS is already an established technique for the treatment of depression, and there is theoretically room for further methodological development towards a high-end therapeutic intervention. In contrast, tDCS is a technically easier method and therefore potentially suitable for wider clinical use. However the evidence of its antidepressant efficacy is less sound, and a recent study found tDCS to be inferior to antidepressant pharmacotherapy. Clinical trials using rTMS for other mental disorders produced mixed findings, whereas tDCS use has not been sufficiently appraised. Conclusion: The most promising results of NIBS have been obtained for depression. These techniques excel in safety and tolerability, although their efficacy still warrants improvement.

The Escitalopram versus Electric Current Therapy for Treating Depression Clinical Study (ELECT-TDCS): rationale and study design of a non-inferiority, triple-arm, placebo-controlled clinical trial / Estudo clínico Escitalopram versus Eletroterapia no Tratamento da Depressão (ELECT-TDCS): racional e desenho de estudo de um ensaio de não inferioridade, de três braços, placebo-controlado

CONTEXT AND OBJECTIVE: Major depressive disorder (MDD) is a common psychiatric condition, mostly treated with antidepressant drugs, which are limited due to refractoriness and adverse effects. We describe the study rationale and design of ELECT-TDCS (Escitalopram versus Electric Current Therapy for Treating Depression Clinical Study), which is investigating a non-pharmacological treatment known as transcranial direct current stimulation (tDCS). DESIGN AND SETTING: Phase-III, randomized, non-inferiority, triple-arm, placebo-controlled study, ongoing in São Paulo, Brazil. METHODS: ELECT-TDCS compares the efficacy of active tDCS/placebo pill, sham tDCS/escitalopram 20 mg/day and sham tDCS/placebo pill, for ten weeks, randomizing 240 patients in a 3:3:2 ratio, respectively. Our primary aim is to show that tDCS is not inferior to escitalopram with a non-inferiority margin of at least 50% of the escitalopram effect, in relation to placebo. As secondary aims, we investigate several biomarkers such as genetic polymorphisms, neurotrophin serum markers, motor cortical excitability, heart rate variability and neuroimaging. RESULTS: Proving that tDCS is similarly effective to antidepressants would have a tremendous impact on clinical psychiatry, since tDCS is virtually devoid of adverse effects. Its ease of use, portability and low price are further compelling characteristics for its use in primary and secondary healthcare. Multimodal investigation of biomarkers will also contribute towards understanding the antidepressant mechanisms of action of tDCS. CONCLUSION: Our results have the potential to introduce a novel technique to the therapeutic arsenal of treatments for depression. .

CONTEXTO E OBJETIVO: O transtorno depressivo maior (TDM) é uma condição psiquiátrica comum, tratada com medicamentos antidepressivos, os quais são limitados devido à refratariedade e efeitos adversos. Descrevemos o racional e o desenho do Estudo Clínico Escitalopram versus Eletroterapia no Tratamento da Depressão (ELECT-TDCS), que investiga um tratamento não farmacológico, conhecido como estimulação transcraniana por corrente contínua (ETCC). DESENHO E LOCAL: Ensaio de fase III, randomizado, de não inferioridade, de três braços, placebo-controlado, em execução em São Paulo, Brasil. MÉTODOS: O estudo compara a eficácia da ETCC ativa/pílula placebo, ETCC simulada/escitalopram 20 mg/dia e ETCC simulada/pílula placebo durante 10 semanas, randomizando 240 pacientes em uma proporção 3:3:2, respectivamente. O objetivo principal é demostrar que a ETCC não é inferior ao escitalopram com uma margem de não inferioridade de pelo menos 50% do efeito de escitalopram em relação ao placebo. Como objetivos secundários, investigamos biomarcadores como polimorfismos genéticos, marcadores séricos, excitabilidade cortical motora, variabilidade da frequência cardíaca e neuroimagem. RESULTADOS: Provar que ETCC é igualmente eficaz a antidepressivos teria um tremendo impacto na psiquiatria clínica, uma vez que a ETCC é praticamente isenta de efeitos adversos. Sua facilidade de uso, portabilidade e preço baixo são outras características atraentes para uso na atenção primária e secundária de saúde. A investigação multimodal de biomarcadores também contribuirá para a compreensão dos mecanismos de ação antidepressivos da ETCC. CONCLUSÃO: Os nossos resultados podem introduzir uma nova técnica no arsenal terapêutico do tratamento da depressão. .