Prevalence and risk factors of psychiatric symptoms and diagnoses before and during the COVID-19 pandemic: findings from the ELSA-Brasil COVID-19 mental health cohort.

BACKGROUND: There is mixed evidence on increasing rates of psychiatric disorders and symptoms during the coronavirus disease 2019 (COVID-19) pandemic in 2020. We evaluated pandemic-related psychopathology and psychiatry diagnoses and their determinants in the Brazilian Longitudinal Study of Health (ELSA-Brasil) São Paulo Research Center. METHODS: Between pre-pandemic ELSA-Brasil assessments in 2008-2010 (wave-1), 2012-2014 (wave-2), 2016-2018 (wave-3) and three pandemic assessments in 2020 (COVID-19 waves in May-July, July-September, and October-December), rates of common psychiatric symptoms, and depressive, anxiety, and common mental disorders (CMDs) were compared using the Clinical Interview Scheduled-Revised (CIS-R) and the Depression Anxiety Stress Scale-21 (DASS-21). Multivariable generalized linear models, adjusted by age, gender, educational level, and ethnicity identified variables associated with an elevated risk for mental disorders. RESULTS: In 2117 participants (mean age 62.3 years, 58.2% females), rates of CMDs and depressive disorders did not significantly change over time, oscillating from 23.5% to 21.1%, and 3.3% to 2.8%, respectively; whereas rate of anxiety disorders significantly decreased (2008-2010: 13.8%; 2016-2018: 9.8%; 2020: 8%). There was a decrease along three wave-COVID assessments for depression [ß = -0.37, 99.5% confidence interval (CI) -0.50 to -0.23], anxiety (ß = -0.37, 99.5% CI -0.48 to -0.26), and stress (ß = -0.48, 99.5% CI -0.64 to -0.33) symptoms (all ps < 0.001). Younger age, female sex, lower educational level, non-white ethnicity, and previous psychiatric disorders were associated with increased odds for psychiatric disorders, whereas self-evaluated good health and good quality of relationships with decreased risk. CONCLUSION: No consistent evidence of pandemic-related worsening psychopathology in our cohort was found. Indeed, psychiatric symptoms slightly decreased along 2020. Risk factors representing socioeconomic disadvantages were associated with increased odds of psychiatric disorders.

[Transcranial electrical brain stimulation methods for treatment of negative symptoms in schizophrenia]. / Transkranielle elektrische Hirnstimulationsverfahren zur Behandlung der Negativsymptomatik bei Schizophrenie.

In recent years noninvasive brain stimulation (NIBS) applications have emerged as a third and novel treatment option alongside psychopharmacology and psychotherapy in the treatment of mental diseases. It is assumed that NIBS could represent a supplement or (in some indications) even replacement to established therapeutic strategies, e.g. in disorders with high resistance to current treatment regimens, such as negative symptoms or cognitive impairments in schizophrenia. Although positive symptoms in schizophrenia can be treated sufficiently with antipsychotic drugs, patients with negative symptoms frequently suffer from persistent lack of impetus, cognitive decline, social withdrawal and loss of global functioning in the activities of daily life; however, in these cases, current treatment strategies exert only moderate effects, and new treatment options are urgently needed. This review article provides a summary of the clinical effects of new electrical NIBS methods, e.g. transcranial direct current stimulation (tDCS), transcranial alternating current stimulation (tACS), and transcranial random noise stimulation (tRNS) for the treatment of negative symptoms in schizophrenia. These new NIBS methods could help restore the disrupted neuronal networks and improve disturbed connectivity, especially of the left dorsolateral prefrontal cortex and left temporoparietal junction. Promising results are reported for the treatment of negative symptoms with tDCS, tACS and tRNS and could thus represent new therapeutic options in the treatment of schizophrenia.

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 for the treatment of post-stroke depression: results from a randomised, sham-controlled, double-blinded trial.

BACKGROUND: Post-stroke depression is a disabling condition occurring in about one-third of patients with stroke. Pharmacological treatments have limited efficacy and important side effects. Recently, transcranial direct current stimulation (tDCS) has shown efficacy in treating depression. This study aimed to assess the efficacy and safety of tDCS for post-stroke depression. METHODS: 48 antidepressant-free patients with post-stroke depression were randomised into two groups (active and sham tDCS). 12 30 min sessions of 2 mA anodal left/cathodal right dorsolateral prefrontal tDCS were administered over 6 weeks (once daily on weekdays for 2 weeks, then 1 session every other week). The primary outcome was the change in the Hamilton Depression Rating Scale (17-items) at 6 weeks. We employed a repeated-measures analysis of variance; the depression score was the dependent variable, and time and group were independent variables. In this intention-to-treat analysis, missing data were addressed according to the last observation carried forward and the mixed-model repeated-measures analysis methods. RESULTS: 5 patients dropped out (two in the active group). Active tDCS was significantly superior to sham at end point (mean difference, 4.7 points; SD=9.21; p<0.001). Response and remission rates were significantly higher in the active (37.5% and 20.8%, respectively) versus the sham (4.1% and 0%, respectively) group, with a number-needed-to-treat of 3 and 5, respectively. CONCLUSIONS: This was the first controlled study to demonstrate that tDCS was safe and effective for post-stroke depression. Therefore, tDCS might be a favourable option for treating these patients. TRIAL REGISTRATION NUMBER: NCT01525524; Results.

Transcranial direct current stimulation for the treatment of post-stroke depression in aphasic patients: a case series.

Aphasia is a common consequence of stroke; it is estimated that about two-thirds of aphasic patients will develop depression in the first year after the stroke. Treatment of post-stroke depression (PSD) is challenging due to the adverse effects of pharmacotherapy and difficulties in evaluating clinical outcomes, including aphasia. Transcranial direct current stimulation (tDCS) is a novel treatment that may improve clinical outcomes in the traditionally pharmacotherapy-refractory PSD. Our aim was to evaluate the safety and efficacy of tDCS for patients with PSD and with aphasia. The Stroke Aphasic Depression Questionnaire (SADQ) and the Aphasic Depression Rating Scale (ADRS) were used to evaluate the severity of PSD. The diagnoses of PSD and aphasia were confirmed by a psychiatrist and a speech-language pathologist, respectively. In this open case series, patients (n = 4) received 10 sessions (once a day) of bilateral tDCS to the dorsolateral prefrontal cortex (DLPFC) and two additional sessions after two and four weeks, for a total of 12 sessions. All patients exhibited improvement in depression after tDCS, as indicated by a decrease in SADQ (47.5%) and in ADRS (65.7%). This improvement was maintained four weeks after the treatment. In this preliminary, open-label study conducted in four PSD patients with aphasia, bilateral tDCS over the DLPFC was shown to induce a substantial mood improvement; tDCS was safe and well tolerated by every patient. Stroke patients with aphasia can be safely treated for PSD with tDCS. Sham-controlled studies are necessary to evaluate this technique further.

Enhancement of affective processing induced by bifrontal transcranial direct current stimulation in patients with major depression.

OBJECTIVE: Our aim was to evaluate whether one single section of transcranial direct current stimulation (tDCS), a neuromodulatory technique that noninvasively modifies cortical excitability, could induce acute changes in the negative attentional bias in patients with major depression. SUBJECTS AND METHODS: Randomized, double-blind, sham-controlled, parallel design enrolling 24 age-, gender-matched, drug-free, depressed subjects. Anode and cathode were placed over the left and right dorsolateral prefrontal cortex. We performed a word Emotional Stroop Task collecting the response times (RTs) for positive-, negative-, and neutral-related words. The emotional Stroop effect for negative vs. neutral and vs. positive words was used as the measure of attentional bias. RESULTS: At baseline, RTs were significantly slower for negative vs. positive words. We found that active but not sham tDCS significantly modified the negative attentional bias, abolishing slower RT for negative words. CONCLUSION: Active but not sham tDCS significantly modified the negative attentional bias. These findings add evidence that a single tDCS session transiently induces potent changes in affective processing, which might be one of the mechanisms of tDCS underlying mood changes.

Ketamine versus electroconvulsive therapy for major depressive episode: An updated systematic review and non-inferiority meta-analysis.

We conducted a systematic review and meta-analysis to investigate the comparative effectiveness of ketamine versus electroconvulsive therapy (ECT) for the treatment of major depressive episodes (MDEs). PubMed, EMBASE and Cochrane Library databases were systematically searched for randomized controlled trials (RCTs) comparing ketamine and ECT for MDE. The primary outcome was response rate, for which we prespecified a non-inferiority margin of -0.1, based on the largest and most recent RCT. Response was defined as a reduction of at least 50 % in the depression scale score. Six RCTs met the inclusion criteria, comprising 655 patients. In the overall population, ketamine was not non-inferior to ECT in response rate (RD -0.10; 95 % CI -0.26 to 0.05; p = 0.198; I2 = 72 %). The ECT group had a higher reduction in depression scores, but without difference in remission and relapse rates. Regarding safety outcomes, ketamine had better posttreatment cognition scores and reduced muscle pain rate compared with ECT, albeit with an increased rate of dissociative symptoms. In a subanalysis with only inpatients, ketamine was inferior to ECT in response rate (RD -0.15; 95 % CI -0.27 to -0.03; p = 0.014; I2 = 25 %), remission, and change in depression scores. These findings support the use of ECT over ketamine for inpatients. Further RCTs are warranted to clarify the comparative effect of these treatments for outpatients.

Home-Use Transcranial Direct Current Stimulation for the Treatment of a Major Depressive Episode: A Randomized Clinical Trial.

Importance: Transcranial direct current stimulation (tDCS) is moderately effective for depression when applied by trained staff. It is not known whether self-applied tDCS, combined or not with a digital psychological intervention, is also effective. Objective: To determine whether fully unsupervised home-use tDCS, combined with a digital psychological intervention or digital placebo, is effective for a major depressive episode. Design, Setting, and Participants: This was a double-blinded, sham-controlled, randomized clinical trial with 3 arms: (1) home-use tDCS plus a digital psychological intervention (double active); (2) home-use tDCS plus digital placebo (tDCS only), and (3) sham home-use tDCS plus digital placebo (double sham). The study was conducted between April 2021 and October 2022 at participants' homes and at Instituto de Psiquiatria do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, Brazil. Included participants were aged 18 to 59 years with major depression and a Hamilton Depression Rating Scale, 17-item version (HDRS-17), score above 16, a minimum of 8 years of education, and access to a smartphone and internet at home. Exclusion criteria were other psychiatric disorders, except for anxiety; neurologic or clinical disorders; and tDCS contraindications. Interventions: tDCS was administered in 2-mA, 30-minute prefrontal sessions for 15 consecutive weekdays (1-mA, 90-second duration for sham) and twice-weekly sessions for 3 weeks. The digital intervention consisted of 46 sessions based on behavioral therapy. Digital placebo was internet browsing. Main Outcomes and Measures: Change in HDRS-17 score at week 6. Results: Of 837 volunteers screened, 210 participants were enrolled (180 [86%] female; mean [SD] age, 38.9 [9.3] years) and allocated to double active (n = 64), tDCS only (n = 73), or double sham (n = 73). Of the 210 participants enrolled, 199 finished the trial. Linear mixed-effects models did not reveal statistically significant group differences in treatment by time interactions for HDRS-17 scores, and the estimated effect sizes between groups were as follows: double active vs tDCS only (Cohen d, 0.05; 95% CI, -0.48 to 0.58; P = .86), double active vs double sham (Cohen d, -0.20; 95% CI, -0.73 to 0.34; P = .47), and tDCS only vs double sham (Cohen d, -0.25; 95% CI, -0.76 to 0.27; P = .35). Skin redness and heat or burning sensations were more frequent in the double active and tDCS only groups. One nonfatal suicide attempt occurred in the tDCS only group. Conclusions and Relevance: Unsupervised home-use tDCS combined with a digital psychological intervention or digital placebo was not found to be superior to sham for treatment of a major depressive episode in this trial. Trial Registration: ClinicalTrials.gov Identifier: NCT04889976.

The sertraline versus electrical current therapy for treating depression clinical study (select-TDCS): results of the crossover and follow-up phases.

BACKGROUND: Transcranial 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). METHODS: Phase 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 performed-every other week for 3 months and, thereafter, once a month for the subsequent 3 months-sessions 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. RESULTS: In 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. CONCLUSION: Continuation tDCS protocols should be optimized as to prevent relapse among tDCS responders, particularly for patients with baseline treatment-resistant depression.

A systematic review and meta-analysis of heart rate variability in epilepsy and antiepileptic drugs.

PURPOSE: Epilepsy is associated with near-fatal and fatal arrhythmias, and sudden unexpected death in epilepsy (SUDEP) is partly related to cardiac events. Dysfunction of the autonomous nervous system causes arrhythmias and, although previous studies have investigated the effects of epilepsy on the autonomic control of the heart, the results are still mixed regarding whether imbalance of sympathetic, vagal, or both systems is present in epilepsy, and also the importance of anticonvulsant treatment on the autonomic system. Therefore, we aimed to investigate epilepsy and its treatment impact on heart rate variability (HRV), assessed by sympathetic and parasympathetic activity expressed as low-frequency (LF) and high-frequency (HF) power spectrum, respectively. METHOD: We performed a systematic review from the first date available to July 2011 in Medline and other databases; key search terms were "epilepsy"; "anticonvulsants"; "heart rate variability"; "vagal"; and "autonomous nervous system." Original studies that reported data and/or statistics of at least one HRV value were included, with data being extracted by two independent authors. We used a random-effects model with Hedges's g as the measurement of effect size to perform two main meta-analyses comparing LF and HF HRV values in (1) epilepsy patients versus controls; (2) patients receiving versus not receiving treatment; and (3) well-controlled versus refractory patients. Secondary analyses assessed other time- and frequency-domain measurements (nonlinear methods were not analyzed due to lack of sufficient data sets). Quality assessment of each study was verified and also meta-analytic techniques to identify and control bias. Meta-regression for age and gender was performed. KEY FINDINGS: Initially, 366 references were identified. According to our eligibility criteria, 30 references (39 studies) were included in our analysis. Regarding HF, epilepsy patients presented lower values (g -0.69) than controls, with the 95% confidence interval (CI) ranging from -1.05 to -0.33. No significant differences were observed for LF (g -0.18; 95% CI -0.71 to 0.35). Patients receiving treatment presented HF values to those not receiving treatment (g -0.05; 95% CI -0.37 to 0.27), with a trend for having higher LF values (g 0.1; 95% CI -0.13 to 0.33), which was more pronounced in those receiving antiepileptic drugs (vs. vagus nerve stimulation). No differences were observed for well-controlled versus refractory patients, possibly due to the low number of studies. Regression for age and gender did not influence the results. Finally, secondary time-domain analyses also showed lower HRV and lower vagal activity in patients with epilepsy, as shown by the standard deviation of normal-to-normal interval (SDNN) and the root mean square of successive differences (RMSSD) indexes, respectively. SIGNIFICANCE: We confirmed and extended the hypothesis of sympathovagal imbalance in epilepsy, as showed by lower HF, SDNN, and RMSSD values when compared to controls. In addition, there was a trend for higher LF values in patients receiving pharmacotherapy. As lower vagal (HF) and higher sympathetic (LF) tone are predictors of morbidity and mortality in cardiovascular samples, our findings highlight the importance of investigating autonomic function in patients with epilepsy in clinical practice. Assessing HRV might also be useful when planning therapeutic interventions, as some antiepileptic drugs can show hazardous effects in cardiac excitability, potentially leading to cardiac arrhythmia.

Repetitive Transcranial Magnetic Stimulation for Major Depressive Disorder in Older Adults: Systematic Review and Meta-analysis.

BACKGROUND: Major depressive disorder (MDD) in older adults is a serious public health concern. Repetitive transcranial magnetic stimulation (rTMS) is a nonpharmacological intervention approved for MDD treatment in adults, but its value in older adults remains unknown. This study aims to systematically review and meta-analyze evidence of rTMS efficacy in MDD treatment among older adults. METHODS: We systematically reviewed the literature for randomized controlled trials (RCTs) and open-label studies assessing rTMS for the treatment of MDD in patients older than 50 years, published until June 2020. Random-effects meta-analyses using standardized mean differences (SMDs) were conducted to assess change in depression severity score (primary outcome), while odds ratios (ORs) were used to assess secondary categorical outcomes (response and remission). Additionally, univariate meta-regression analyses were performed to identify potential predictors of change in depression severity scores. RESULTS: Fourteen RCTs were included in meta-analyses and 26 studies (10 RCTs and 16 open-label studies) in meta-regression. Active rTMS was significantly superior to sham treatment for reduction of severity (SMD = 0.36; 95% CI = 0.13-0.60), as well as response (OR = 3.26; 95% CI = 2.11-5.04) and remission (OR = 4.63; 95% CI = 2.24-9.55). Studies were of moderate to high quality, with funnel plots and Egger's regression test not suggestive of publication bias. In meta-regressions, higher mean age and number of sessions were significantly associated with greater improvement. CONCLUSIONS: Our results support that rTMS is an effective, safe, and well-tolerated treatment for MDD in older adults and that it should be considered in the treatment of this vulnerable population.

The Effects of Transcranial Direct Current Stimulation in Obsessive-Compulsive Disorder Symptoms: A Meta-Analysis and Integrated Electric Fields Modeling Analysis.

Transcranial direct current stimulation (tDCS) has been showing promising effects for the treatment of obsessive-compulsive disorder (OCD), but there is still no conclusion on its efficacy for this disorder. We performed a systematic review and meta-analysis of trials using tDCS for OCD and a computer modeling analysis to evaluate the electric field (EF) strengths of different electrode assemblies in brain regions of interest (ROIs) (PROSPERO-42021262465). PubMed/MEDLINE, Embase, Cochrane Library and Web of Science databases were searched from inception to 25 September 2022. Randomized controlled trials (RCTs) and open-label studies were included. The primary aim was the effect size (Hedges' g) of continuous outcomes and potential moderators of response. For EF modeling, SimNIBS software was used. Four RCTs and four open-label trials were included (n = 241). Results revealed a large effect of tDCS in the endpoint, but no significant effect between active and sham protocols. No predictor of response was found. EF analysis revealed that montages using the main electrode over the (pre)supplementary motor area with an extracephalic reference electrode might lead to stronger EFs in the predefined ROIs. Our results revealed that tDCS might be a promising intervention to treat OCD; however, larger studies are warranted.

Efficacy of Transcranial Direct Current Stimulation to Improve Insight in Patients With Schizophrenia: A Systematic Review and Meta-analysis of Randomized Controlled Trials.

BACKGROUND AND HYPOTHESIS: Impaired insight into the illness and its consequences is associated with poor outcomes in schizophrenia. While transcranial direct current stimulation (tDCS) may represent a potentially effective treatment strategy to relieve various symptoms of schizophrenia, its impact on insight remains unclear. To investigate whether tDCS would modulate insight in patients with schizophrenia, we undertook a meta-analysis based on results from previous RCTs that investigated the clinical efficacy of tDCS. We hypothesize that repeated sessions of tDCS will be associated with insight improvement among patients. STUDY DESIGN: PubMed and ScienceDirect databases were systematically searched to identify RCTs that delivered at least 10 tDCS sessions in patients with schizophrenia. The primary outcome was the change in insight score, assessed by the Positive and Negative Syndrome Scale (PANSS) item G12 following active tDCS sessions as opposed to sham stimulation. Effect sizes were calculated for all studies and pooled using a random-effects model. Meta-regression and subgroup analyses were conducted. STUDY RESULTS: Thirteen studies (587 patients with schizophrenia) were included. A significant pooled effect size (g) of -0.46 (95% CI [-0.78; -0.14]) in favor of active tDCS was observed. Age and G12 score at baseline were identified as significant moderators, while change in total PANSS score was not significant. CONCLUSIONS: Ten sessions of active tDCS with either frontotemporoparietal or bifrontal montage may improve insight into the illness in patients with schizophrenia. The effect of this treatment could contribute to the beneficial outcomes observed in patients following stimulation.

A study protocol for an ongoing multi-arm, randomized, double-blind, sham-controlled clinical trial with digital features, using portable transcranial electrical stimulation and internet-based behavioral therapy for major depression disorders: The PSYLECT study.

BACKGROUND: Transcranial electrical stimulation (tES) is considered effective and safe for depression, albeit modestly, and prone to logistical burdens when performed in external facilities. Investigation of portable tES (ptES), and potentiation of ptES with remote psychological interventions have shown positive, but preliminary, results. RESEARCH DESIGN: We report the rationale and design of an ongoing multi-arm, randomized, double-blind, sham-controlled clinical trial with digital features, using ptES and internet-based behavioral therapy (iBT) for major depressive disorder (MDD) (NCT04889976). METHODS: We will evaluate the efficacy, safety, tolerability and usability of (1) active ptES + active iBT ('double-active'), (2) active ptES + sham iBT ('ptES-only'), and (3) sham ptES + sham iBT ('double-sham'), in adults with MDD, with a Hamilton Depression Rating Scale - 17 item version (HDRS-17) score ≥ 17 at baseline, during 6 weeks. Antidepressants are allowed in stable doses during the trial. RESULTS: We primarily co-hypothesize changes in HDRS-17 will be greater in (1) 'double-active' compared to 'ptES-only,' (2) 'double-active' compared to 'double-sham,' and (3) 'ptES-only' compared to 'double-sham.' We aim to enroll 210 patients (70 per arm). CONCLUSIONS: Our results should offer new insights regarding the efficacy and scalability of combined ptES and iBT for MDD, in digital mental health.

Treatment of depression in the elderly with repetitive transcranial magnetic stimulation using theta-burst stimulation: Study protocol for a randomized, double-blind, controlled trial.

Introduction: Transcranial magnetic stimulation (TMS) is a consolidated procedure for the treatment of depression, with several meta-analyses demonstrating its efficacy. Theta-burst stimulation (TBS) is a modification of TMS with similar efficacy and shorter session duration. The geriatric population has many comorbidities and a high prevalence of depression, but few clinical trials are conducted specifically for this age group. TBS could be an option in this population, offering the advantages of few side effects and no pharmacological interactions. Therefore, our aim is to investigate the efficacy of TBS in geriatric depression. Clinical trial registration: [https://clinicaltrials.gov/ct2/], identifier [NCT04842929].

Medical cannabinoids for treatment of neuropsychiatric symptoms in dementia: a systematic review.

INTRODUCTION: Neuropsychiatric symptoms are an integral component of the natural history of dementia, occurring from prodromal to advanced stages of the disease process and causing increased burden and morbidity. Clinical presentations are pleomorphic and clinical management often requires combinations of pharmacological and non-pharmacological interventions. However, limited efficacy and a non-negligible incidence of adverse psychotropic drug events emphasize the need for novel therapeutic options. OBJECTIVES: To review the evidence supporting use of medical cannabinoids for treatment of neuropsychiatric symptoms (NPS) of dementia. METHODS: We conducted a systematic review of the medical literature to examine scientific publications reporting use of medical cannabinoids for treatment of NPS. Medical Subject Headings (MeSH) were used to search for relevant publications and only papers reporting original clinical information were included. A secondary search was performed within selected publications to capture relevant citations that were not retrieved by the systematic review. The papers selected were categorized according to the level of evidence generated by the studies in relation to this clinical application, i.e. (1) controlled clinical trials; (2) open-label or observational studies; and (3) case reports. RESULTS: Fifteen publications with original clinical data were retrieved: five controlled clinical trials, three open-label/observational studies, and seven case reports. Most studies indicated that use of medical cannabinoids engendered favorable outcomes for treatment of NPS related to moderate and advanced stages of dementia, particularly agitation, aggressive behavior, sleep disorder, and sexual disinhibition. CONCLUSION: Medical cannabinoids constitute a promising pharmacological approach to treatment of NPS with preliminary evidence of benefit in at least moderate to severe dementia. Controlled trials with longitudinal designs and larger samples are required to examine the long-term efficacy of these drugs in different types and stages of dementia, in addition to their adverse events and risk of interactions with other drugs. Many pharmacological details are yet to be determined, such as dosing, treatment duration, and concentrations of active compounds (e.g., cannabidiol [CBD]/ Δ9-tetrahydrocannabinol [THC] ratio) in commercial preparations of medical cannabinoids.

Treatment of mixed depression with theta-burst stimulation (TBS): results from a double-blind, randomized, sham-controlled clinical trial.

Mixed depression is probably different in terms of clinical course and response to treatment. Repetitive transcranial magnetic stimulation (rTMS) is well established in non-mixed depression, and theta-burst stimulation (TBS) protocol is replacing conventional protocols because of noninferiority and reduced delivery time. However, TBS has not been adequately studied in mixed states. This study was a double-blind, six-week, sham-controlled, and randomized clinical trial of bilateral TBS targeting the right and left dorsolateral prefrontal cortex, respectively. Adults with bipolar and major depressive disorder experiencing an acute mixed depression were eligible if they had not benefited from a first- or second-line treatment for acute unipolar or bipolar depression recommended by the Canadian Network for Mood and Anxiety Treatments. Out of 100 patients included, 90 composed modified intention-to-treat sample, which was patients that completed at least one week of the intervention. There were no significant differences in Montgomery-Asberg depression rating scale score changes (least squares mean difference between groups at week 3, -0.06 [95% CI, - 3.39 to 3.51; P = 0.97] in favor of sham TBS). Response and remission rates per MADRS were also not statistically different among active and sham groups (35.7% vs. 43.7%, and 28.5% vs. 37.5% respectively at week 6, ps > 0.51). No other analyses from baseline to weeks 3 or 6 revealed significant time x group interaction or mean differences among groups in the mITT sample. Bilateral TBS targeting the DLPFC is not efficacious as an add-on treatment of acute bipolar and unipolar mixed depression. ClinicalTrials.govIdentifier: NCT04123301.

Adjunctive Therapy to Manage Neuropsychiatric Symptoms in Moderate and Severe Dementia: Randomized Clinical Trial Using an Outpatient Version of Tailored Activity Program.

BACKGROUND: Neuropsychiatric symptoms (NPS) such as aggression, apathy, agitation, and wandering may occur in up to 90%of dementia cases. International guidelines have suggested that non-pharmacological interventions are as effective as pharmacological treatments, however without the side effects and risks of medications. An occupational therapy method, called Tailored Activity Program (TAP), was developed with the objective to treat NPS in the elderly with dementia and has been shown to be effective. OBJECTIVE: Evaluate the efficacy of the TAP method (outpatient version) in the treatment of NPS in individuals with dementia and in the burden reduction of their caregivers. METHODS: This is a randomized, double-blind, controlled clinical trial for the treatment of NPS in dementia. Outcome measures consisted of assessing the NPS of individuals with dementia, through the Neuropsychiatric Inventory-Clinician rating scale (NPI-C), and assessing the burden on their caregivers, using the Zarit Scale. All the participants were evaluated pre-and post-intervention. RESULTS: 54 individuals with dementia and caregivers were allocated to the experimental (n = 28) and control (n = 26) groups. There was improvement of the following NPS in the experimental group: delusions, agitation, aggressiveness, depression, anxiety, euphoria, apathy, disinhibition, irritability, motor disturbance, and aberrant vocalization. No improvement was observed in hallucinations, sleep disturbances, and appetite disorders. The TAP method for outpatient settings was also clinically effective in reducing burden between caregivers of the experimental group. CONCLUSION: The use of personalized prescribed activities, coupled with the caregiver training, may be a clinically effective approach to reduce NPS and caregiver burden of individuals with dementia.

Cognitive outcomes after tDCS in schizophrenia patients with prominent negative symptoms: Results from the placebo-controlled STARTS trial.

Cognitive deficits and negative symptoms in schizophrenia are associated with poor functional outcomes and limited in terms of treatment. The Schizophrenia Treatment With Electric Transcranial Stimulation (STARTS) trial has shown efficacy of transcranial direct current stimulation (tDCS) for improving negative symptoms. In this secondary analysis, we investigate its effects on cognitive performance. In STARTS, a double-blinded, sham-controlled, randomized clinical trial, patients were treated with twice-daily, 20-min, 2-mA fronto-temporal tDCS over 5 days or sham-tDCS. In 90 patients, we evaluated the cognitive performance up to 12 weeks post-treatment. We found that active-tDCS showed no beneficial effects over sham-tDCS in any of the tests. Based on a 5-factor cognitive model, improvements of executive functions and delayed memory were observed in favor of sham-tDCS. Overall, the applied active-tDCS protocol, primarily designed to improve negative symptoms, did not promote cognitive improvement. We discuss possible protocol modification potentially required to increase tDCS effects on cognition. ClinicalTrials.gov identifier: NCT02535676.

Effects of transcranial direct current stimulation (tDCS) and concurrent cognitive training on episodic memory in patients with traumatic brain injury: a double-blind, randomised, placebo-controlled study.

INTRODUCTION: Deficits in episodic memory following traumatic brain injury (TBI) are common and affect independence in activities of daily living. Transcranial direct current stimulation (tDCS) and concurrent cognitive training may contribute to improve episodic memory in patients with TBI. Although previous studies have shown the potential of tDCS to improve cognition, the benefits of the tDCS applied simultaneously to cognitive training in participants with neurological disorders are inconsistent. This study aims to (1) investigate whether active tDCS combined with computer-assisted cognitive training enhances episodic memory compared with sham tDCS; (2) compare the differences between active tDCS applied over the left dorsolateral prefrontal cortex (lDLPFC) and bilateral temporal cortex (BTC) on episodic memory and; (3) investigate inter and intragroup changes on cortical activity measured by quantitative electroencephalogram (qEEG). METHODS AND ANALYSIS: A randomised, parallel-group, double-blind placebo-controlled study is conducted. Thirty-six participants with chronic, moderate and severe closed TBI are being recruited and randomised into three groups (1:1:1) based on the placement of tDCS sponges and electrode activation (active or sham). TDCS is applied for 10 consecutive days for 20 min, combined with a computer-based cognitive training. Cognitive scores and qEEG are collected at baseline, on the last day of the stimulation session, and 3 months after the last tDCS session. We hypothesise that (1) the active tDCS group will improve episodic memory scores compared with the sham group; (2) differences on episodic memory scores will be shown between active BTC and lDLPFC and; (3) there will be significant delta reduction and an increase in alpha waves close to the location of the active electrodes compared with the sham group. ETHICS AND DISSEMINATION: This study was approved by Hospital das Clínicas, University of São Paulo Ethical Institutional Review Border (CAAE: 87954518.0.0000.0068). TRIAL REGISTRATION NUMBER: NCT04540783.