Adriano H. Moffa

Transcranial direct current stimulation in psychiatric disorders

The interest in non-invasive brain stimulation techniques is increasing in recent years. Among these techniques, transcranial direct current stimulation (tDCS) has been the subject of great interest among researchers because of its easiness to use, low cost, benign profile of side effects and encouraging results of research in the field. This interest has generated several studies and randomized clinical trials, particularly in psychiatry. In this review, we provide a summary of the development of the technique and its mechanism of action as well as a review of the methodological aspects of randomized clinical trials in psychiatry, including studies in affective disorders, schizophrenia, obsessive compulsive disorder, child psychiatry and substance use disorder. Finally, we provide an overview of tDCS use in cognitive enhancement as well as a discussion regarding its clinical use and regulatory and ethical issues. Although many promising results regarding tDCS efficacy were described, the total number of studies is still low, highlighting the need of further studies aiming to replicate these findings in larger samples as to provide a definite picture regarding tDCS efficacy in psychiatry.

Repetitive Transcranial Magnetic Stimulation for the Acute Treatment of Major Depressive Episodes: A Systematic Review With Network Meta-analysis

Importance Although several strategies of repetitive transcranial magnetic stimulation (rTMS) have been investigated as treatment of major depressive disorder (MDD), their comparative efficacy and acceptability is unknown. Objective To establish the relative efficacy and acceptability of the different modalities of rTMS used for MDD by performing a network meta-analysis, obtaining a clinically meaningful treatment hierarchy. Data Sources PubMed/MEDLINE, EMBASE, PsycInfo, and Web of Science were searched up until October 1, 2016. Study Selection Randomized clinical trials that compared any rTMS intervention with sham or another rTMS intervention. Trials performing less than 10 sessions were excluded. Data Extraction and Synthesis Two independent reviewers used standard forms for data extraction and quality assessment. Random-effects, standard pairwise, and network meta-analyses were performed to synthesize data. Main Outcomes and Measures Response rates and acceptability (dropout rate). Remission was the secondary outcome. Effect sizes were reported as odds ratios (ORs) with 95% CIs. Results Eighty-one studies (4233 patients, 59.1% women, mean age of 46 years) were included. The interventions more effective than sham were priming low-frequency (OR, 4.66; 95% CI, 1.70-12.77), bilateral (OR, 3.96; 95% CI, 2.37-6.60), high-frequency (OR, 3.07; 95% CI, 2.24-4.21), &thgr;-burst stimulation (OR, 2.54; 95% CI, 1.07-6.05), and low-frequency (OR, 2.37; 95% CI, 1.52-3.68) rTMS. Novel rTMS interventions (accelerated, synchronized, and deep rTMS) were not more effective than sham. Except for &thgr;-burst stimulation vs sham, similar results were obtained for remission. All interventions were at least as acceptable as sham. The estimated relative ranking of treatments suggested that priming low-frequency and bilateral rTMS might be the most efficacious and acceptable interventions among all rTMS strategies. However, results were imprecise and relatively few trials were available for interventions other than low-frequency, high-frequency, and bilateral rTMS. Conclusions and Relevance Few differences were found in clinical efficacy and acceptability between the different rTMS modalities, favoring to some extent bilateral rTMS and priming low-frequency rTMS. These findings warrant the design of larger RCTs investigating the potential of these approaches in the short-term treatment of MDD. Current evidence cannot support novel rTMS interventions as a treatment for MDD. Trial Registration clinicaltrials.gov Identifier: PROSPERO CRD42015019855.

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.)

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.

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

To evaluate whether and to which extent skin redness (erythema) affects investigator blinding in transcranial direct current stimulation (tDCS) trials.

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 (&bgr;int = −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

Cognitive effects of transcranial direct current stimulation treatment in patients with major depressive disorder: An individual patient data meta-analysis of randomised, sham-controlled trials

HighlightsIt remains unclear whether tDCS treatment has cognitive benefits in depression.This individual patient data meta‐analysis examined effects from seven RCTs.Active tDCS treatment did not cause cognitive benefits compared to sham. &NA; Transcranial direct current stimulation (tDCS) has emerged as a promising new treatment for major depression. While recent randomised, sham‐controlled studies found tDCS to have antidepressant effects, it remains to be determined whether a tDCS treatment course may also enhance cognitive function independent of mood effects in depressed patients. This systematic review and individual patient data (IPD) meta‐analysis examined cognitive outcomes from randomised, sham‐controlled trials of tDCS treatment for major depression. Seven randomised, sham‐controlled trials (n = 478 participants, 260 in active and 218 in sham) of tDCS for major depression were included. Results showed no cognitive enhancement after active tDCS compared to sham for the 12 cognitive outcomes investigated. Active relative to sham tDCS treatment was associated with reduced performance gains on a measure of processing speed (&bgr; = −0.33, 95% CI −0.58; −0.08, p = 0.011). Active tDCS treatment for depression did not show cognitive benefits independent of mood effects. Rather, tDCS treatment relative to sham stimulation for major depression may instead be associated with a reduced practice effect for processing speed.

Safety and acceptability of transcranial direct current stimulation for the acute treatment of major depressive episodes: Analysis of individual patient data

BACKGROUND Transcranial direct current stimulation (tDCS) is a non-invasive brain stimulation modality that has been increasingly used for major depressive disorder (MDD) treatment. Although studies in healthy volunteers showed that the technique is well-tolerated, tDCS safety and acceptability have not been sufficiently explored in patients with MDD. METHODS We collected individual patient data from 6 randomized clinical trials that had been previously identified in a systematic review and meta-analysis. Primary outcomes were safety (rate of adverse events) and acceptability (rate of dropouts). Secondary outcomes were clinical, demographic and treatment predictors of the primary outcomes. RESULTS Dropout rates between active (8.8%) and sham (12%) groups were not significantly different (OR= 0.7, p=0.38). Adverse event rates between active (73.5%) and sham (68.3%) groups were not significantly different (OR= 1.4, p= 0.23). Higher current densities were associated with lower adverse event rates. LIMITATIONS Dropout reasons were not systematically reported and adverse events were not collected using questionnaires standardized across studies. CONCLUSIONS Active tDCS is as acceptable and safe as sham tDCS, as found in randomized clinical trials of MDD.

Evidence for increased motor cortical facilitation and decreased inhibition in atypical depression.

Major depressive disorder (MDD) is a clinically heterogeneous condition. However, the role of cortical glutamate and gamma‐aminobutyric acid (GABA) receptor‐mediated activity, implicated in MDD pathophysiology, has not been explored in different MDD subtypes. Our aim was to assess the atypical and melancholic depression subtypes regarding potential differences in GABA and glutamate receptor‐mediated activity through established transcranial magnetic stimulation (TMS) neurophysiological measures from the motor cortex.

Novel neurotherapeutics in psychiatry: use and rationale of transcranial direct current stimulation in major depressive disorder

Background : Transcranial direct current stimulation (tDCS) is a novel non-pharmacological intervention being investigated for the treatment of major depressive disorder (MDD). Objective : To perform an updated review of tDCS for MDD. Method : Systematic review in Medline/PubMed and other databases of all clinical studies evaluating the clinical efficacy of tDCS in MDD, from the first date available to December/2013. Results : Out of 55 articles, 24 were included, being 6 open-label studies; 8 randomized, double-blind, sham-controlled trials; 2 follow-up studies; 2 meta-analyses and 6 case reports. We observed an improvement of 20-40% in depressive symptoms, being slightly better in open studies. Five randomized clinical trials displayed positive results. The meta-analyses presented mixed results; although none included the study of Brunoni et al. (2013) that represents almost 50% of the evaluated sample. Open-label studies and case reports also investigated tDCS in bipolar depression, post-stroke depression and employed different parameters of stimulation. Discussion : TDCS is a novel, promising treatment for MDD. Definite evidence from large, ongoing clinical trials will be available in the next years.