An electric field modeling study with meta-analysis to understand the antidepressant effects of transcranial direct current stimulation (tDCS)

Objective: Transcranial direct current stimulation (tDCS) has mixed effects for major depressive disorder (MDD) symptoms, partially owing to large inter-experimental variability in tDCS protocols and their correlated induced electric fields (E-fields). We investigated whether the E-field strength of distinct tDCS parameters was associated with antidepressant effect. Methods: A meta-analysis was performed with placebo-controlled clinical trials of tDCS enrolling MDD patients. PubMed, EMBASE, and Web of Science were searched from inception to March 10, 2023. Effect sizes of tDCS protocols were correlated with E-field simulations (SimNIBS) of brain regions of interest (bilateral dorsolateral prefrontal cortex [DLPFC] and bilateral subgenual anterior cingulate cortex [sgACC]). Moderators of tDCS responses were also investigated. Results: A total of 20 studies were included (21 datasets, 1,008 patients), using 11 distinct tDCS protocols. Results revealed a moderate effect for MDD (g = 0.41, 95%CI 0.18-0.64), while cathode position and treatment strategy were found to be moderators of response. A negative association between effect size and tDCS-induced E-field magnitude was seen, with stronger E-fields in the right frontal and medial parts of the DLPFC (targeted by the cathode) leading to smaller effects. No association was found for the left DLPFC and the bilateral sgACC. An optimized tDCS protocol is proposed. Conclusions: Our results highlight the need for a standardized tDCS protocol in MDD clinical trials. Registration number: PROSPERO CRD42022296246.

Treatment resistance in schizophrenia: a meta-analysis of prevalence and correlates

Objectives: To determine the prevalence and correlates of treatment-resistant schizophrenia (TRS) through a systematic review and meta-analysis. Methods: Following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) criteria, an electronic search was performed in PubMed and Embase through May 17, 2022. All study designs that assessed a minimum of 20 schizophrenia-spectrum patients and provided data on TRS prevalence or allowed its calculation were included. Estimates were produced using a random-effects model meta-analysis. Results: The TRS prevalence across 50 studies (n = 29,390) was 36.7% (95%CI 33.1-40.5, p < 0.0001). The prevalence ranged from 22% (95%CI 18.4-25.8) in first-episode to 39.5% (95%CI 32.2-47.0) in multiple-episode samples (Q = 18.27, p < 0.0001). Primary treatment resistance, defined as no response from the first episode, was 23.6% (95%CI 20.5-26.8) vs. 9.3% (95%CI 6.8-12.2) for later-onset/secondary (≥ 6 months after initial treatment response). Longer illness duration and recruitment from long-term hospitals or clozapine clinics were associated with higher prevalence estimates. In meta-regression analyses, older age and poor functioning predicted greater TRS. When including only studies with lower bias risk, the TRS prevalence was 28.4%. Conclusion: Different study designs and recruitment strategies accounted for most of the observed heterogeneity in TRS prevalence rates. The results point to early-onset and later-onset TRS as two separate disease pathways requiring clinical attention. Registration number: PROSPERO CRD42018092033.

Distractibility, anxiety, irritability, and agitation symptoms are associated with the severity of depressive and manic symptoms in mixed depression

Objective: To explore whether there is an association between distractibility, anxiety, irritability, and agitation (DAIA) symptoms and the severity of depressive and manic symptoms. Methods: Patients with unipolar and bipolar disorder (I and II) and mixed depression were evaluated. DAIA symptoms were assessed using previously described definitions. Results: The full analysis set comprised 100 patients. The severity of depressive symptoms in mixed depression, assessed by Montgomery-Åsberg Depression Rating Scale (MADRS), was significantly associated with the presence of two or more DAIA symptoms in the bipolar sample, influenced mainly by anxiety. The severity of manic symptoms in mixed depression, assessed by Young Mania Rating Scale (YMRS), was significantly associated with the presence of two or more DAIA symptoms in the bipolar sample and three or four DAIA symptoms in the unipolar sample. Conclusion: DAIA symptoms were associated with greater severity of manic symptoms in mixed depression. DAIA symptoms must be evaluated in all patients with mixed features and are associated with the severity of depressive and manic symptoms in mixed depression. Clinical trial registration: ClinicalTrials.gov (NCT04123301).

Neurocircuit models of obsessive-compulsive disorder: limitations and future directions for research

Obsessive-compulsive disorder (OCD) is a common psychiatric condition classically characterized by obsessions (recurrent, intrusive and unwanted thoughts) and compulsions (excessive, repetitive and ritualistic behaviors or mental acts). OCD is heterogeneous in its clinical presentation and not all patients respond to first-line treatments. Several neurocircuit models of OCD have been proposed with the aim of providing a better understanding of the neural and cognitive mechanisms involved in the disorder. These models use advances in neuroscience and findings from neuropsychological and neuroimaging studies to suggest links between clinical profiles that reflect the symptoms and experiences of patients and dysfunctions in specific neurocircuits. Several models propose that treatments for OCD could be improved if directed to specific neurocircuit dysfunctions, thereby restoring efficient neurocognitive function and ameliorating the symptomatology of each associated clinical profile. Yet, there are several important limitations to neurocircuit models of OCD. The purpose of the current review is to highlight some of these limitations, including issues related to the complexity of brain and cognitive function, the clinical presentation and course of OCD, etiological factors, and treatment methods proposed by the models. We also provide suggestions for future research to advance neurocircuit models of OCD and facilitate translation to clinical application.

Chronic inflammatory diseases, subclinical atherosclerosis, and cardiovascular diseases: Design, objectives, and baseline characteristics of a prospective case-cohort study ‒ ELSA-Brasil

Abstract Objectives This analysis describes the protocol of a study with a case-cohort to design to prospectively evaluate the incidence of subclinical atherosclerosis and Cardiovascular Disease (CVD) in Chronic Inflammatory Disease (CID) participants compared to non-diseased ones. Methods A high-risk group for CID was defined based on data collected in all visits on self-reported medical diagnosis, use of medicines, and levels of high-sensitivity C-Reactive Protein >10 mg/L. The comparison group is the Aleatory Cohort Sample (ACS): a group with 10% of participants selected at baseline who represent the entire cohort. In both groups, specific biomarkers for DIC, markers of subclinical atherosclerosis, and CVD morbimortality will be tested using weighted Cox. Results The high-risk group (n = 2,949; aged 53.6 ± 9.2; 65.5% women) and the ACS (n=1543; 52.2±8.8; 54.1% women) were identified. Beyond being older and mostly women, participants in the high-risk group present low average income (29.1% vs. 24.8%, p < 0.0001), higher BMI (Kg/m2) (28.1 vs. 26.9, p < 0.0001), higher waist circumference (cm) (93.3 vs. 91, p < 0.0001), higher frequencies of hypertension (40.2% vs. 34.5%, p < 0.0001), diabetes (20.7% vs. 17%, p = 0.003) depression (5.8% vs. 3.9%, p = 0.007) and higher levels of GlycA a new inflammatory marker (p < 0.0001) compared to the ACS. Conclusions The high-risk group selected mostly women, older, lower-income/education, higher BMI, waist circumference, and of hypertension, diabetes, depression, and higher levels of GlycA when compared to the ACS. The strategy chosen to define the high-risk group seems adequate given that multiple sociodemographic and clinical characteristics are compatible with CID.

Appraising the effectiveness of electrical and magnetic brain stimulation techniques in acute major depressive episodes: an umbrella review of meta-analyses of randomized controlled trials

Electrical and magnetic brain stimulation techniques present distinct mechanisms and efficacy in the acute treatment of depression. This was an umbrella review of meta-analyses of randomized controlled trials of brain stimulation techniques for managing acute major depressive episodes. A systematic review was performed in the PubMed/MEDLINE databases from inception until March 2020. We included the English language meta-analysis with the most randomized controlled trials on the effects of any brain stimulation technique vs. control in adults with an acute depressive episode. Continuous and dichotomous outcomes were assessed. A Measurement Tool to Assess Systematic Reviews-2 was applied and the credibility of evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation framework. Seven meta-analyses were included (5,615 patients), providing evidence for different modalities of brain stimulation techniques. Three meta-analyses were evaluated as having high methodological quality, three as moderate, and one as low. The highest quality of evidence was found for high frequency-repetitive transcranial magnetic stimulation (rTMS), transcranial direct current stimulation, and bilateral rTMS. There is strong clinical research evidence to guide future clinical use of some techniques. Our results confirm the heterogeneity of the effects across these techniques, indicating that different mechanisms of action lead to different efficacy profiles.

COMVC-19: A Program to protect healthcare workers' mental health during the COVID-19 Pandemic. What we have learned

OBJECTIVE: In 2020, the COVID-19 pandemic brought a work and stress overload to healthcare workers, increasing their vulnerability to mental health impairments. In response, the authors created the COMVC-19 program. The program offered preventive actions and mental health treatment for the 22,000 workers of The Hospital das Clinicas da Faculdade de Medicina da Universidade de São Paulo (HCFMUSP). This paper aims to describe its implementation and share what we have learned from this experience. METHODS: Workers were able to easily access the program through a 24/7 hotline. Additionally, a mobile phone app that screened for signs and symptoms of emotional distress and offered psychoeducation and/or referral to treatment was made available. Data from both these sources as well as any subsequent psychiatric evaluations were collected. RESULTS: The first 20 weeks of our project revealed that most participants were female, and part of the nursing staff working directly with COVID-19 patients. The most frequently reported symptoms were: anxiety, depression and sleep disturbances. The most common diagnoses were Adjustment, Anxiety, and Mood disorders. CONCLUSIONS: Implementing a mental health program in a multimodal intervention was feasible in a major quaternary public hospital. Our data also suggests that preventive actions should primarily be aimed at anxiety and depression symptoms, with a particular focus on the nursing staff.

Association of BDNF, HTR2A, TPH1, SLC6A4, and COMT polymorphisms with tDCS and escitalopram efficacy: ancillary analysis of a double-blind, placebo-controlled trial

Objective: We investigated whether single nucleotide polymorphisms (SNPs) associated with neuroplasticity and activity of monoamine neurotransmitters, such as the brain-derived neurotrophic factor (BDNF, rs6265), the serotonin transporter (SLC6A4, rs25531), the tryptophan hydroxylase 1 (TPH1, rs1800532), the 5-hydroxytryptamine receptor 2A (HTR2A, rs6311, rs6313, rs7997012), and the catechol-O-methyltransferase (COMT, rs4680) genes, are associated with efficacy of transcranial direct current stimulation (tDCS) in major depression. Methods: Data from the Escitalopram vs. Electrical Current Therapy for Treating Depression Clinical Study (ELECT-TDCS) were used. Participants were antidepressant-free at baseline and presented with an acute, moderate-to-severe unipolar depressive episode. They were randomized to receive escitalopram/tDCS-sham (n=75), tDCS/placebo-pill (n=75), or placebo-pill/sham-tDCS (n=45). General linear models assessed the interaction between treatment group and allele-wise carriers. Additional analyses were performed for each group and each genotype separately. Results: Pairwise group comparisons (tDCS vs. placebo, tDCS vs. escitalopram, and escitalopram vs. placebo) did not identify alleles associated with depression improvement. In addition, exploratory analyses also did not identify any SNP unequivocally associated with improvement of depression in any treatment group. Conclusion: Larger, combined datasets are necessary to identify candidate genes for tDCS response.

Non-invasive brain stimulation therapies / Terapias de neuroestimulação não invasivas

Noninvasive brain stimulation therapies are a promising field for the development of new protocols for the treatment of neuropsychiatric disorders. They are based on the stimulation of neural networks with the intent of modeling their synaptic activity to adequate levels. For this, it is necessary to precisely determine which networks are related to which brain functions, and the normal activation level of each of these networks, so that it is possible to direct the stimulation to the affected networks in order to induce the desired effects. These relationships are under intense investigation by the scientific community, and will contribute to the advancement of treatments by neurostimulation, with the emergence of increasingly accurate and effective protocols for different disorders. Currently, the most used techniques are Transcranial Direct Current Stimulation and Transcranial Magnetic Stimulation, with the most common applications being for treating Major Depressive Disorder. The advancement of research in this field may determine new target networks for stimulation in the treatment of other disorders, extending the application of these techniques and also our knowledge about brain functioning.

As terapias biológicas não invasivas se apresentam como um campo promissor para o desenvolvimento de novos protocolos de tratamento de transtornos neuropsiquiátricos. Elas se baseiam na estimulação de redes neurais com intuito de modular sua atividade sináptica para níveis adequados. Para isso, é necessário a determinação precisa de quais redes estão relacionadas a quais funções cerebrais, e do nível de ativação normal de cada uma dessas redes, para que então seja possível direcionar a estimulação às redes afetadas a fim de induzir os efeitos desejados. Essas relações estão sob intensa investigação pela comunidade científica, e vão contribuir para o avanço dos tratamentos por neuroestimulação, com o surgimento de protocolos cada vez mais precisos e efetivos para diferentes transtornos. Atualmente, as técnicas mais utilizadas são a Estimulação Transcraniana por Corrente Contínua e a Estimulação Magnética Transcraniana, sendo a aplicação mais comum no tratamento do Transtorno Depressivo Maior. O avanço das pesquisas possivelmente determinará novas redes alvo para estimulação no tratamento de outros transtornos, estendendo a aplicação dessas técnicas e também do nosso conhecimento sobre o funcionamento cerebral.

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.

Early psychiatric morbidity in a Brazilian sample of acute ischemic stroke patients

OBJECTIVE: Stroke is a major public health problem worldwide, and its neuropsychiatric sequelae are frequent and disabling. Furthermore, there is evidence that these sequelae impair recovery. Brazil has the highest stroke rates in Latin America, but data on the frequency of neuropsychiatric disorders in these patients are scarce. This study aimed to identify mental disorders among in-hospital patients with acute ischemic stroke. METHODS: The Mini International Neuropsychiatric Interview-Plus (MINI-Plus) was applied to 60 patients during the first week of hospitalization. RESULTS: Psychiatric disorders were diagnosed in 55% of the patients. A wide range of neuropsychiatric disorders have been identified, mainly mood and anxiety disorders. Specifically, we identified major depression (26.7%), alcohol abuse or dependence (11.7%), specific phobia (8.3%), generalized anxiety disorder (6.7%), psychosis (5.0%), social phobia (3.3%), adjustment disorder (3.3%) and panic disorder (1.7%). CONCLUSION: Psychiatric comorbidity should be evaluated as part of the rehabilitation of stroke patients and should be carefully examined by physicians.

Primum non nocere or primum facere meliorem? Hacking the brain in the 21st century / Primum non nocere ou primum facem meliorem? O cérebro pirateado do século 21

Abstract Transcranial direct current stimulation (tDCS) is a non-invasive brain stimulation technique that modulates cortical excitability. It is devoid of serious adverse events and exerts variable effects on cognition, with several research findings suggesting that it can improve memory, verbal and mathematical skills. Because tDCS devices are low-cost, portable and relatively easy to assemble, they have become available outside of the medical setting and used for non-medical ("cosmetic") purposes by laypersons. In this sense, tDCS has become a popular technique aiming to improve cognition and the achievement of a better performance not only at work, but also in other fields such as sports, leisure activities (video games) and even the military. In spite of these unforeseen developments, there has been a general paralysis of the medical and regulatory agencies to develop guidelines for the use of tDCS for cosmetic purposes. Several challenges are present, most importantly, how to restrict tDCS use outside of the medical setting in face of variable and sometimes conflicting results from scientific research. This article aims to describe the popular use of tDCS, in light of the pillars of neuroethics, a branch of bioethics relative to brain research. Between two possible but extreme solutions - total release or total restriction of tDCS - it is paramount to develop a spectrum of alternatives, which may vary over time and in different cultural backgrounds.

Resumo A estimulação transcraniana por corrente contínua (ETCC) é uma técnica não invasiva de estimulação cerebral que modula a excitabilidade cortical. A ETCC é desprovida de efeitos adversos graves e exerce efeitos variáveis sobre a cognição, com vários achados de pesquisa sugerindo que a técnica pode promover melhora nas habilidades mnêmica, verbal e matemática. Devido ao seu baixo custo, portabilidade e facilidade de montagem, os aparelhos de ETCC tornaram-se disponíveis fora do contexto médico, sendo usados para fins não médicos ("cosméticos") por indivíduos leigos. Nesse sentido, a ETCC tornou-se um procedimento popular para aprimoramento da cognição e a realização de melhor desempenho não somente no ambiente de trabalho, mas também em campos tais como o esporte, atividades de lazer ( video games ) e até no meio militar. Apesar desses acontecimentos imprevisíveis, há uma certa morosidade das agências médicas e regulatórias em desenvolver diretrizes para o uso de ETCC para fins cosméticos. Há muitos desafios presentes, principalmente, como restringir o uso da ETCC fora do contexto médico em face de resultados variáveis, e muitas vezes conflitantes, da pesquisa científica sobre o tema. Este artigo tem como objetivo descrever o uso popular da ETCC sob a luz da neuroética, um ramo da bioética que se dedica ao estudo do cérebro. Entre duas situações possíveis, mas extremas - liberação ou restrição totais da ETCC -, é primordial o desenvolvimento de um espectro de alternativas, que podem variar ao longo do tempo e depender de diversos contextos culturais.

Psychopathological evaluation and use of the Hospital Anxiety and Depression Scale in a sample of Brazilian patients with post-stroke depression

Abstract Background: Depression is the most frequent psychiatric complication of stroke and is often undetected or inadequately treated. Objective: This study aimed to characterize psychopathological aspects of Brazilian patients admitted to an acute stroke unit, and to evaluate the performance of the Hospital Anxiety and Depression Scale (HADS) in detecting cases of depression. Methods: This was a cross-sectional study. Sixty consecutive patients admitted to an acute stroke unit were assessed with the National Institutes of Health Stroke Scale, the Modified Rankin Scale, the Functional Independence Measure, the Mini International Neuropsychiatric Interview-Plus, the HADS, the Mini Mental State Examination (MMSE) and the Pathological Laughing and Crying Scale. Results: Prevalence of depression was 26.7%. Patients with post-stroke depression were more likely to present diabetes (p < 0.01) and had greater disability (p < 0.001) and cognitive impairment (p < 0.001) in comparison to non-depressed patients. Depressed patients showed worse performance specifically on tasks of attention/calculation and language of the MMSE. ROC curve analysis of HADS provided a cutoff value of 6 for detecting depression (sensitivity: 83.3%; specificity: 83.3%). The depression subscale of HADS (HADS-D) presented sensitivity of 100% and specificity of 99.17%. Discussion: HADS-D showed good performance in screening for depressive symptoms after acute stroke.

Common mental disorders and sociodemographic characteristics: baseline findings of the Brazilian Longitudinal Study of Adult Health (ELSA-Brasil)

Objective: To assess the prevalence of common mental disorders (CMD) and the association of CMD with sociodemographic characteristics in the Brazilian Longitudinal Study of Adult Health (ELSA-Brasil) cohort. Methods: We analyzed data from the cross-sectional baseline assessment of the ELSA-Brasil, a cohort study of 15,105 civil servants from six Brazilian cities. The Clinical Interview Schedule-Revised (CIS-R) was used to investigate the presence of CMD, with a score ≥ 12 indicating a current CMD (last week). Specific diagnostic algorithms for each disorder were based on the ICD-10 diagnostic criteria. Prevalence ratios (PR) of the association between CMD and sociodemographic characteristics were estimated by Poisson regression. Results: CMD (CIS-R score ≥ 12) was found in 26.8% (95% confidence intervals [95%CI] 26.1-27.5). The highest burden occurred among women (PR 1.9; 95%CI 1.8-2.0), the youngest (PR 1.7; 95%CI 1.5-1.9), non-white individuals, and those without a university degree. The most frequent diagnostic category was anxiety disorders (16.2%), followed by depressive episodes (4.2%). Conclusion: The burden of CMD was high, particularly among the more socially vulnerable groups. These findings highlight the need to strengthen public policies aimed to address health inequities related to mental disorders.

Post stroke depression: clinics, etiopathogenesis and therapeutics

Background Stroke is a major cause of morbidity and mortality worldwide. Neuropsychiatric disorders are often associated with stroke and, among them, depression is the most prevalent. Post-stroke Depression (PSD) is related to disability, failure in returning to work, impairment in interpersonal functioning and mortality. Its etiopathogenesis is still uncertain, as well as its treatment. In Brazil, there are few data on the impact of PSD. Objective This work is dedicated to conduct a comprehensive review of the concept of PSD, its pathophysiology, morbidity and treatment. Methods PubMed, Medline and Lilacs searches of relevant terms yielded 3,265 papers in the last 10 years. We selected original studies and reviews that addressed the aspects mentioned above. Results We present the history of the notion of PSD and describe its epidemiology, looking to highlight Brazilian studies. Diagnostic criteria and clinical presentation were detailed, with emphasis on cognitive aspects. The four main pathophysiological theories proposed to PSD are presented and we discuss the various treatment strategies, involving psychopharmacologic options, brain stimulation techniques and psychotherapy. Discussion This work provides comprehensive information on PSD, of great utility for clinical practice and research in this topic.