A novel approach for targeting the left dorsolateral prefrontal cortex for transcranial magnetic stimulation using a cognitive task.

Repetitive transcranial magnetic stimulation (rTMS) has the potential to be developed as a novel treatment for cognitive dysfunction. However, current methods of targeting rTMS for cognition fail to consider inter-individual functional variability. This study explored the use of a cognitive task to individualise the target site for rTMS administered to the left dorsolateral prefrontal cortex (L-DLPFC). Twenty-five healthy participants were enrolled in a sham-controlled, crossover study. Participants performed a random letter generation task under the following conditions: no stimulation, sham and active 'online' rTMS applied to F3 (International 10-20 System) and four standardised surrounding sites. Across all sites combined, active 'online' rTMS was associated with significantly reduced performance compared to sham rTMS for unique trigrams (p = 0.012), but not for unique digrams (p > 0.05). Using a novel localisation methodology based on performance outcomes from both measures, a single optimal individualised site was identified for 92% [n = 23] of participants. At the individualised site, performance was significantly poorer compared to a common standard site (F3) and both control conditions (ps < 0.01). The current results suggest that this localisation methodology using a cognitive task could be used to individualise the rTMS target site at the L-DLPFC for modulating and potentially enhancing cognitive functioning.

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 .).

A systematic review and meta-analysis on the effects of transcranial direct current stimulation in depressive episodes.

BACKGROUND: Transcranial direct current stimulation (tDCS) has shown mixed results for depression treatment. OBJECTIVE: To perform a systematic review and meta-analysis of trials using tDCS to improve depressive symptoms. METHODS: A systematic review was performed from the first date available to January 06, 2020 in PubMed, EMBASE, Cochrane Library, and additional sources. We included randomized, sham-controlled clinical trials (RCTs) enrolling participants with an acute depressive episode and compared the efficacy of active versus sham tDCS, including association with other interventions. The primary outcome was the Hedges' g for continuous depression scores; secondary outcomes included odds ratios (ORs) and number needed to treat (NNT) for response, remission, and acceptability. Random effects models were employed. Sources of heterogeneity were explored via metaregression, sensitivity analyses, subgroup analyses, and bias assessment. RESULTS: We included 23 RCTs (25 datasets, 1,092 participants), most (57%) presenting a low risk of bias. Active tDCS was superior to sham regarding endpoint depression scores (k = 25, g = 0.46, 95% confidence interval [CI]: 0.22-0.70), and also achieved superior response (k = 18, 33.3% vs. 16.56%, OR = 2.28 [1.52-3.42], NNT = 6) and remission (k = 18, 19.12% vs. 9.78%, OR = 2.12 [1.42-3.16], NNT = 10.7) rates. Moreover, active tDCS was as acceptable as sham. No risk of publication bias was identified. Cumulative meta-analysis showed that effect sizes are basically unchanged since total sample reached 439 participants. CONCLUSIONS: TDCS is modestly effective in treating depressive episodes. Further well-designed, large-scale RCTs are warranted.

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.

Transcranial Direct Current Stimulation in the Acute Depressive Episode: A Systematic Review of Current Knowledge.

Major depressive disorder is a severe, refractory mental disorder. Only one third of patients treated with antidepressants achieve remission after 3 trials, while subject to adverse effects. Therefore, the investigation of alternative treatments is paramount. The aim of this systematic review was to summarize the most recent evidence of transcranial direct current stimulation (tDCS) intervention for the acute phase of major depressive disorder. A PubMed search was performed including the terms "transcranial direct current stimulation" OR "transcranial direct stimulation" OR "tDCS" AND "major depressive disorder" OR "major depression" OR "depression" AND "trial." The search was conducted from inception until February 2018. Our search yielded initially 165 results, and 14 randomized clinical trials were included according to eligibility criteria. Most studies were pilot studies, with mixed findings. Two large randomized clinical trials recently published also presented primary negative findings. Study protocols usually used anodal left/cathodal right dorsolateral prefrontal cortex stimulation, 1 to 2.5 mA, and 5 to 20 tDCS sessions. We discuss the limitations of the included trials, such as sample and tDCS parameters heterogeneity between studies. To conclude, tDCS seems to be safe and devoid of serious adverse effects, although robust efficacy has not been consistently demonstrated in clinical trials assessing an acute treatment course of up to 4 weeks. Further directions are discussed, such as parameter individualization, investigation of biological markers, and home-use tDCS.

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.

Transcranial direct current stimulation for acute major depressive episodes: meta-analysis of individual patient data.

BACKGROUND: Transcranial direct current stimulation (tDCS) is a non-pharmacological intervention for depression. It has mixed results, possibly caused by study heterogeneity. AIMS: To assess tDCS efficacy and to explore individual response predictors. METHOD: Systematic review and individual patient data meta-analysis. RESULTS: Data were gathered from six randomised sham-controlled trials, enrolling 289 patients. Active tDCS was significantly superior to sham for response (34% v. 19% respectively, odds ratio (OR) = 2.44, 95% CI 1.38-4.32, number needed to treat (NNT) = 7), remission (23.1% v. 12.7% respectively, OR = 2.38, 95% CI 1.22-4.64, NNT = 9) and depression improvement (B coefficient 0.35, 95% CI 0.12-0.57). Mixed-effects models showed that, after adjustment for other predictors and confounders, treatment-resistant depression and higher tDCS 'doses' were, respectively, negatively and positively associated with tDCS efficacy. CONCLUSIONS: The effect size of tDCS treatment was comparable with those reported for repetitive transcranial magnetic stimulation and antidepressant drug treatment in primary care. The most important parameters for optimisation in future trials are depression refractoriness and tDCS dose.

Impact of two or less missing treatment sessions on tDCS clinical efficacy: results from a factorial, randomized, controlled trial in major depression.

OBJECTIVES: Transcranial direct current stimulation (tDCS) is a neuromodulatory intervention with recent clinical trials showing promising results in major depression treatment. Although tDCS has some appealing characteristics (e.g., low cost, ease of use, and relatively benign profile of adverse effects), one important drawback of the technique is the need to deliver consecutive, repeated sessions for several weekdays. However, no study investigated whether absences during this acute treatment phase impact on tDCS efficacy, and, if so, whether absences should be considered dropouts, therefore increasing attrition. MATERIAL AND METHODS: To examine this issue, we used data from a randomized, factorial, sham-controlled tDCS study that recruited 120 depressed patients. In this trial, the acute treatment phase consisted of ten consecutive sessions delivered once daily from Monday to Friday; two nonconsecutive missed visits were allowed, with extra tDCS sessions being performed to complete the original number of sessions. RESULTS: Our main finding was that the procedure of granting one to two absences during the acute treatment phase did not impact on tDCS antidepressant efficacy. Moreover, out of 103 completers, only 41 (39.8%) patients presented no missing visits and 25 (24.3%) presented two absences. These patients did not differ in clinical and demographic characteristics; thus, absences were probably circumstantial (e.g., traffic congestion, personal obligations). CONCLUSIONS: Absences during the acute tDCS treatment phase are common, which support the use of flexible schedules in future tDCS trials as to minimize attrition. Also, further studies should access whether higher number of absences can compromise optimal tDCS efficacy.

Individualised Transcranial Magnetic Stimulation Targeting of the Left Dorsolateral Prefrontal Cortex for Enhancing Cognition: A Randomised Controlled Trial.

Repetitive transcranial magnetic stimulation (rTMS) has been demonstrated to produce cognitive enhancing effects across different neuropsychiatric disorders; however, so far, these effects have been limited. This trial investigated the efficacy of using a novel individualised approach to target the left dorsolateral prefrontal cortex (L-DLPFC) for enhancing cognitive flexibility based on performance on a cognitive task. First, forty healthy participants had their single target site at the L-DLPFC determined based on each individual's performance on a random letter generation task. Participants then received, in a cross-over single-blinded experimental design, a single session of intermittent theta burst stimulation (iTBS) to their individualised DLPFC target site, an active control site and sham iTBS. Following each treatment condition, participants completed the Task Switching task and Colour-Word Stroop test. There was no significant main effect of treatment condition on the primary outcome measure of switch reaction times from the Task Switching task [F = 1.16 (2, 21.6), p = 0.33] or for any of the secondary cognitive outcome measures. The current results do not support the use of our novel individualised targeting methodology for enhancing cognitive flexibility in healthy participants. Research into alternative methodological targeting approaches is required to further improve rTMS's cognitive enhancing effects.

Neuromodulatory effects of theta burst stimulation to the prefrontal cortex.

Theta burst stimulation (TBS) is a new form of repetitive transcranial magnetic stimulation (TMS) capable of non-invasively modulating cortical excitability. In recent years TBS has been increasingly used as a neuroscientific investigative tool and therapeutic intervention for psychiatric disorders, in which the dorsolateral prefrontal cortex (DLPFC) is often the primary target. However, the neuromodulatory effects of TBS on prefrontal regions remain unclear. Here we share EEG and ECG recordings and structural MRI scans, including high-resolution DTI, from twenty-four healthy participants who received intermittent TBS (two sessions), continuous TBS (two sessions), and sham stimulation (one session) applied to the left DLPFC using a single-blinded crossover design. Each session includes eyes-open resting-state EEG and single-pulse TMS-EEG obtained before TBS and 2-, 15-, and 30-minutes post-stimulation. This dataset enables foundational basic science investigations into the neuromodulatory effects of TBS on the DLPFC.

Efficacy and acceptability of transcranial direct current stimulation (tDCS) for major depressive disorder: An individual patient data meta-analysis.

We evaluated the efficacy and acceptability of transcranial direct current stimulation (tDCS) for treating acute depressive episodes using individual patient data that provide more precise estimates than aggregate data meta-analysis. A systematic review of placebo-controlled trials on tDCS as only intervention was conducted until December-2018. Data from each study was collated to estimate odds ratio (OR) and number needed to treat (NNT) of response and remission, and depression improvement. Endpoints were pre-determined. Nine eligible studies (572 participants), presenting moderate/high certainty of evidence, were included. Active tDCS was significantly superior to sham for response (30.9% vs. 18.9% respectively; OR = 1.96, 95%CI [1.30-2.95], NNT = 9), remission (19.9% vs. 11.7%, OR = 1.94 [1.19-3.16], NNT = 13) and depression improvement (effect size of ß = 0.31, [0.15-0.47]). Moreover, continuous clinical improvement was observed even after the end of acute tDCS treatment. There were no differences in all-cause discontinuation rates and no predictors of response were identified. To conclude, active tDCS was statistically superior to sham in all outcomes, although its clinical effects were moderate.

Cognitive changes after tDCS and escitalopram treatment in major depressive disorder: Results from the placebo-controlled ELECT-TDCS trial.

BACKGROUND: Cognitive deficits in major depressive disorder (MDD) are associated with low quality of life and higher suicide risk. Antidepressant drugs have modest to null effects in improving such deficits. Therefore, we investigated the cognitive effects of transcranial direct current stimulation (tDCS), which is a promising antidepressant non-pharmacological intervention, in MDD. METHODS: An exploratory analysis on cognitive performance was conducted in 243 depressed patients from the Escitalopram vs. Electric Current Therapy for Treating Depression Clinical Study (ELECT-TDCS), a sham-controlled study comparing the efficacy of tDCS vs. escitalopram. A neuropsychological battery was applied at baseline and endpoint (10 weeks of treatment) to create composite cognitive scores (processing speed, working memory, and verbal fluency). Linear mixed regression models were used to evaluate changes according to intervention groups, adjusted for confounding variables (age, years of schooling, gender, and benzodiazepine use) and depression improvement. RESULTS: No cognitive deterioration was observed in any group. Patients receiving tDCS presented reduced practice gains compared to placebo in processing speed. In patients receiving escitalopram vs. placebo and in the subgroup of clinical responders (>50% depression improvement from baseline), those receiving tDCS vs. placebo presented increased performance in verbal fluency. No significant differences between tDCS and escitalopram groups were detected. LIMITATIONS: Absence of healthy controls. CONCLUSION: Prefrontal tDCS did not lead to cognitive deficits in depressed patients, although it reduced practice effects in processing speed. tDCS responders presented increased performance in verbal fluency. Further investigation of tDCS cognitive effects in depression is warranted.

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.

Transcranial Direct Current Stimulation in Psychiatric Disorders: A Comprehensive Review.

Transcranial direct current stimulation (tDCS) is a noninvasive brain stimulation technique that has been gaining favor as a viable tool in Psychiatry. The purpose of this review is to summarize the evidence of tDCS as a treatment of disorders such as depression, schizophrenia, and obsessive-compulsive disorder (OCD). Current findings indicate that tDCS is probably effective in non-treatment-resistant depressive patients. Regarding schizophrenia and OCD, present evidence is not robust enough, although preliminary results indicate that tDCS is a promising technique. Therefore, more trials are needed before using tDCS in a clinical setting.

A systematic review and meta-analysis on placebo response to repetitive transcranial magnetic stimulation for depression trials.

BACKGROUND: Although several studies indicate that placebo response is large to antidepressant pharmacotherapy in major depressive disorder (MDD), no updated meta-analysis has quantified the magnitude of the placebo (sham) response to repetitive transcranial magnetic stimulation (rTMS) in MDD yet. OBJECTIVE: To conduct a systematic review and meta-analysis on this issue in randomized controlled trials (RCTs) involving participants with MDD; and to explore potential moderators. METHODOLOGY: PubMed/MEDLINE, Embase, PsycINFO, and Web of Science electronic databases were searched from inception up to March 15, 2017 for RCTs that investigated the efficacy of any rTMS modality compared to sham intervention in participants with acute depressive episodes. Cochrane Risk of Bias Tool was used to estimate risks. We estimated the placebo effect size (Hedges's g, random-effects model) response using placebo groups baseline and endpoint depressive symptom scores. Meta-regressions have been employed to explore potential moderators of response. RESULTS: Sixty-one studies met eligibility criteria (N=1328; mean age, 47years; 57% females). Placebo response was large (g=0.8, 95% CI=0.65-0.95, p<0.01) regardless of the modality of intervention. Placebo response was directly associated with publication year and depression improvement of the active group, and inversely associated with higher levels of treatment-resistant depression. Other moderators, including gender, age, and stimulator type, were not associated with the outcome. Overall, 24.6%, 67.2%, and 8.2% of studies had an overall low, unclear, and high bias risk, respectively. CONCLUSION: Placebo response in rTMS depression trials was large and associated with depression improvement of the active treatment group. Such result suggests that excluding placebo responders with a run-in phase may not confer advantage since response to 'active' rTMS may decrease as well. Moreover, placebo response may be a component of therapeutic response to rTMS in MDD. In addition, placebo response increase over time could indicate improvement in rTMS trial designs, including better sham rTMS methods.

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.

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.

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), θ-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 θ-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.