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OBJECTIVE: Few studies have focused on medical students and residents' mental health impact on medical residency selection (MRS) performance. The authors evaluated the association of performance in MRS with depressive and anxiety symptoms and with a reported psychiatric diagnosis (rPD). METHODS: The authors enrolled candidates after the second round of MRS examinations at a Brazilian Medical School. Performance was assessed by final grade. Depressive and anxiety symptoms were assessed by the Quick Inventory of Depressive Symptomatology Self-Report (QIDS-SR) and the State-Trait Anxiety Inventory (STAI). The authors performed mediation analysis and multiple linear regression analysis to investigate the impact of rPD, state and trait anxiety, and depressive symptom severity on performance. RESULTS: 515 of the 643 MRS candidates (80.1%) participated in the study. Higher age, attending a preparatory course for MRS, rPD, and the number of MRS applications that year were associated with poorer performance. In mediation analysis, trait anxiety was associated with a direct effect on performance and an indirect effect mediated by rPD. CONCLUSION: The data suggest that psychiatric diagnosis is associated with poorer performance on MRS, regardless of current symptoms of anxiety and depression. Additionally, increased levels of trait anxiety may negatively impact performance, directly and indirectly.

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Background: Depressive symptoms have been associated with cognitive impairment after stroke, and women may be specifically affected. Objective: The aim of this study was to investigate gender-specific characteristics in the relationship between changes in depression severity and changes in cognitive performance after stroke. Methods: We prospectively evaluated 73 patients without a previous history of depression in the first and fourth months after a first ischemic stroke. The severity of depressive symptoms was assessed using the 31-item version of the Hamilton Rating Scale for Depression, and executive function, attention, working memory, and verbal fluency were assessed using a neuropsychological battery. Results: We included 46 (63.0%) men and 27 (36.9%) women, with mean ages of 55.2 (SD ± 15.1) and 46.8 (SD ± 14.7) years, respectively. We found significant improvement in the digit span forward and Stroop dots from month 1 to month 4 post stroke for both men and women. Women, but not men, presented a correlation between changes in phonemic verbal fluency and changes in the 31-item version of the Hamilton Rating Scale for Depression scores. Improvement in depression was correlated with improvement in verbal fluency, and worsening in depression was correlated with worsening in verbal fluency. Conclusions: Our results suggest that women might be more vulnerable to the relationship between depressive symptoms and cognitive performance, and improvement of depression may be necessary for women's improvement in phonemic verbal fluency from the first to the fourth month after a stroke. We did not adjust the results for multiple comparisons. Thus, our findings might be considered preliminary, and confirmatory studies, also focusing on specific characteristics of women that could explain these differences, are warranted.

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OBJECTIVE: The objective of this study was to assess the quality of clinical practice guidelines (CPGs) for the pharmacological treatment of depression along with their recommendations and factors associated with higher quality. DESIGN: We conducted a systematic review that included CPGs for the pharmacological treatment of depression in adults. DATA SOURCES: We searched for publications from 1 January 2011 to 31 December 2021, in MEDLINE, Cochrane Library, Embase, PsycINFO, BVS and 12 other databases and guideline repositories. ELIGIBILITY CRITERIA FOR SELECTING STUDIES: We included CPGs containing recommendations for the pharmacological treatment of depression in adults at outpatient care setting, regardless of whether it met the U.S. National Academy of Medicine criteria, or not. If a CPG included recommendations for both children and adults, they were considered. No language restriction was applied. DATA EXTRACTION AND SYNTHESIS: Data extraction was also conducted independently and in duplicate, a process that was validated in a previous project. The quality of the CPGs and their recommendations were assessed by three independent reviewers using Appraisal of Guidelines for Research and Evaluation (AGREE II) and Appraisal of Guidelines for Research and Evaluation-Recommendations Excellence (AGREE-REX). A CPG was considered to be of high quality if AGREE II Domain 3 was ≥60%; while their recommendations were considered high if AGREE-REX Domain 1 was ≥60%. RESULTS: Seventeen out of 63 (27%) CPGs were classified as high quality, while 7 (11.1%) had high-quality recommendations. The factors associated with higher-scoring CPGs and recommendations in the multiple linear regression analyses were 'Handling of conflicts of interest', 'Multiprofessional team' and 'Type of institution'. 'Inclusion of patient representative in the team' was also associated with higher-quality recommendations. CONCLUSIONS: The involvement of professionals from diverse backgrounds, the handling of conflicts of interest, and the inclusion of patients' perspectives should be prioritised by developers aiming for high-quality CPGs for the treatment of depression.

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INTRODUCTION: Depression is a serious and widespread mental health disorder. A significant proportion of patients with depression fail to remit after two antidepressant treatment trials, a condition named treatment-resistant depression (TRD). Clinical practice guidelines (CPGs) are instruments aimed to improve diagnosis and treatment. This study objective is to systematically appraise the quality and elaborate a comparison of high-quality CPGs with high-quality recommendations aimed at TRD. METHODS AND ANALYSIS: We searched several specialized databases and organizations that develop CPGs. Independent researchers assessed the quality of the CPGs and their recommendations using AGREE II and AGREE-REX instruments, respectively. We selected only high-quality CPGs that included definition and recommendations for TRD. We investigated their divergencies and convergencies as well as weak and strong points. RESULTS: Among seven high-quality CPGs with high-quality recommendations only two (Germany's Nationale Versorgungs Leitlinie-NVL and US Department of Veterans Affairs and Department of Defense-VA/DoD) included specific TRD definition and were selected. We found no convergent therapeutic strategy among these two CPGs. Electroconvulsive therapy is recommended by the NVL but not by the VA/DoD, while repetitive transcranial magnetic stimulation is recommended by the VA/DoD but not by the NVL. While the NVL recommends the use of lithium, and a non-routine use of thyroid or other hormones, psychostimulants, and dopaminergic agents the VA/DoD does not even include these drugs among augmentation strategies. Instead, the VA/DoD recommends ketamine or esketamine as augmentation strategies, while the NVL does not mention these drugs. Other differences between these CPGs include antidepressant combination, psychotherapy as a therapeutic augmentation, and evaluation of the need for hospitalization all of which are only recommended by the NVL. CONCLUSIONS: High-quality CPGs for the treatment of depression diverge regarding the definition and use of the term TRD. There is also no convergent approach to TRD from currently high-quality CPGs.

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BACKGROUND: Burnout, by definition, is related to adverse chronic workplace stressors. Life events outside the workplace have been associated with an increased risk of psychiatric morbidity. However, it is unknown whether life events outside the workplace increase the severity of burnout. PURPOSE: The aim of the study was to investigate the association between burnout and life events outside the workplace in nursing assistants. METHODS: In an observational, cross-sectional, single-site study of 521 nursing assistants at a university hospital, we assessed burnout with the Maslach Burnout Inventory-Human Services Survey, and life events with the Social Readjustment Rating Scale. We constructed equations of multiple linear regression analyses that included each burnout subscale as the dependent variable and a domain of life events as the independent variable. Results were adjusted for potential confounders, including gender, no religion or faith, years of work, and depression. RESULTS: An increase in the number of life events in the domain of personal changes or difficulties (e.g., personal injury or illness, sexual difficulties, change in recreation, church activities, social activities, sleeping habits, eating habits and revision of personal habits) was associated with increased severity of emotional exhaustion. An increase in the number of life events in the domain of changes in familial situation and in the domains of death of relatives or friends were associated with increased severity of depersonalization. Those associations were independent of work-related life events and other potential confounders. CONCLUSIONS: Life events outside the workplace may increase the levels of burnout in nursing assistants.

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INTRODUCTION: Depression is a serious and widespread mental health disorder. Although effective treatment does exist, a significant proportion of patients with depression fail to respond to antidepressant treatment trials, a condition named treatment-resistant depression. Efficient approach should be given this condition in order to revert the burden caused by depression. Clinical practice guidelines (CPGs) are evidence-based health promotion instruments to improve diagnosis and treatment. CPGs recommendations for treatment-resistant depression must be trustworthy. The objective of the proposed study is to systematically identify, appraise the quality of CPGs for the treatment of depression and elaborate a synthesis of recommendations for treatment-resistant depression of CPGs considered to be of high quality and with high quality recommendations. METHODS AND ANALYSIS: We will search the databases of organizations, such as PubMed, Embase, Cochrane Library, PsycInfo, and the Virtual Health Library, and organizations that develop CPGs. Three independent researchers will assess the quality of the CPGs and their recommendations using the AGREE II and AGREE-REX instruments, respectively. Given the identification of divergences and convergences as well as weak and strong points among high quality CPGs, our work may help developers, clinicians and eventually patients. ETHICS AND DISSEMINATION: No ethical approval is required for a systematic review, as no patient data will be used. The research results will be disseminated in conferences and submitted to a peer reviewed journal.

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OBJECTIVE: To assess similarities and differences in the recommended sequence of strategies among the most relevant clinical practice guidelines (CPGs) for the treatment of depression in adults with inadequate response to first-line treatment. DATA SOURCES: We performed a systematic review of the literature spanning January 2011 to August 2020 in Medline, Embase, Cochrane Library and 12 databases recognised as CPGs repositories. CPGs quality was assessed using the Appraisal of Guidelines for Research and Evaluation II (AGREE II). STUDY SELECTION: The eligibility criteria were CPGs that described pharmacological recommendations for treating depression for individuals aged 18 years or older in outpatient care setting. We included CPGs considered of high-quality (≥80% in domain 3 of AGREE II) or recognised as clinically relevant. DATA EXTRACTION: Two independent researchers extracted recommendations for patients who did not respond to first-line pharmacological treatment from the selected CPGs. RESULTS: We included 46 CPGs and selected 8, of which 5 were considered high quality (≥80% in domain 3 of AGREE II) and 3 were recognised as clinically relevant. Three CPGs did not define inadequate response to treatment and 3 did not establish a clear sequence of strategies. The duration of treatment needed to determine that a patient had not responded was not explicit in 3 CPGs and was discordant in 5 CPGs. Most CPGs agree in reassessing the diagnosis, assessing the presence of comorbidities, adherence to treatment, and increase dosage as first steps. All CPGs recommend psychotherapy, switching antidepressants, and considering augmentation/combining antidepressants. CONCLUSION: Relevant CPGs present shortcomings in recommendations for non-responders to first-line antidepressant treatment including absence and divergencies in definition of inadequate response and sequence of recommended strategies. Overall, most relevant CPGs recommend reassessing the diagnosis, evaluate comorbidities, adherence to treatment, increase dosage of antidepressants, and psychotherapy as first steps. PROSPERO REGISTRATION NUMBER: CRD42016043364.

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Background: Ketamine has been shown to produce a rapid and robust antidepressant effect. Though numerous routes of administration have been studied, subcutaneous (SC) has proven to be a convenient and cost-effective route making its use particularly relevant in developing countries. Here we provide a systematic review covering the use of SC racemic ketamine and esketamine in depression, including its efficacy, safety and tolerability. Methods: A systematic literature search was carried out, from inception through March, 2021, using PubMed/MEDLINE, EMBASE and Web of Science, with no limits of language. After identifying 159 potentially relevant articles, 12 articles were selected after applying our inclusion/exclusion criteria. These comprised two randomized clinical trials, five case-reports and five retrospective studies. Given the small number of studies found and their heterogeneous nature, a meta-analysis was not considered appropriate. Here we provide a synthesis of these data including participant characteristics, dose range, efficacy, safety/ tolerability. Risk of bias was accessed using the Cochrane risk of bias tool. Results: SC Ketamine was administered to unipolar and bipolar patients a single or multiple doses, weekly or twice-weekly, a dose-titration approach was made in major studies, dose ranged from 0.1 to 0.5 mg/Kg of racemic ketamine and 0.5-1 mg/Kg of esketamine. Across all studies, SC ketamine showed a rapid and robust antidepressant effect, with response/ remission rates from 50 to 100% following both single or multiple doses, with transitory side effects. Conclusion: SC racemic ketamine and esketamine in depression is a promising strategy showing beneficial efficacy and tolerability. Future studies exploring the SC route, its cost-effectiveness, and a direct comparison with IV and intranasal (IN) protocols are warranted. Systematic Review Registration: CRD42019137434.

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Current first-line treatments for major depressive disorder (MDD) include pharmacotherapy and cognitive-behavioral therapy. However, one-third of depressed patients do not achieve remission after multiple medication trials, and psychotherapy can be costly and time-consuming. Although non-implantable neuromodulation (NIN) techniques such as transcranial magnetic stimulation, transcranial direct current stimulation, electroconvulsive therapy, and magnetic seizure therapy are gaining momentum for treating MDD, the efficacy of non-convulsive techniques is still modest, whereas use of convulsive modalities is limited by their cognitive side effects. In this context, we propose that NIN techniques could benefit from a precision-oriented approach. In this review, we discuss the challenges and opportunities in implementing such a framework, focusing on enhancing NIN effects via a combination of individualized cognitive interventions, using closed-loop approaches, identifying multimodal biomarkers, using computer electric field modeling to guide targeting and quantify dosage, and using machine learning algorithms to integrate data collected at multiple biological levels and identify clinical responders. Though promising, this framework is currently limited, as previous studies have employed small samples and did not sufficiently explore pathophysiological mechanisms associated with NIN response and side effects. Moreover, cost-effectiveness analyses have not been performed. Nevertheless, further advancements in clinical trials of NIN could shift the field toward a more "precision-oriented" practice.

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Depression affects over 300 million individuals worldwide and is responsible for most of the 800,000 annual suicides. Clinical practice guidelines (CPGs) for treatment of depression, founded on scientific evidence, are essential to improve patient care. However, economic and sociocultural factors may influence CPG elaboration, potentially leading to divergences in their recommendations. Consequently, we analyzed pharmacological recommendations for the treatment of depression from the most relevant CPGs. We included four CPGs with scores ≥ 80% for Domain 3 (rigor of development) on the Appraisal of Guidelines for Research and Evaluation and two other commonly used CPGs. The recommendations, their strengths, and the level of evidence were extracted from each CPG by two independent researchers and grouped as follows: (1) general recommendations for the pharmacological treatment for depression (suicide risk, acute treatment, continuation and maintenance phases, and treatment discontinuation); (2) treatment of non-responsive or partially responsive patients; and (3) treatment for subtypes of depression (chronic, psychotic, catatonic, melancholic, seasonal, somatic, mixed, and atypical). Only 50% of CPGs included recommendations for the risk of suicide associated with pharmacotherapy. All CPGs included serotonin selective reuptake inhibitors (SSRIs) as first-line treatment; however, one CPG also included agomelatine, milnacipran, and mianserin as first-line alternatives. Recommendations for depression subtypes (catatonic, atypical, melancholic) were included in three CPGs. The strength of recommendation and level of evidence clearly differed among CPGs, especially regarding treatment augmentation strategies. We conclude that, although CPGs converged in some recommendations (e.g., SSRIs as first-line treatment), they diverged in cardinal topics including the absence of recommendations regarding the risk of suicide associated with pharmacotherapy. Consequently, the recommendations listed in a specific CPG should be followed with caution.

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Current first-line treatments for major depressive disorder (MDD) include pharmacotherapy and cognitive-behavioral therapy. However, one-third of depressed patients do not achieve remission after multiple medication trials, and psychotherapy can be costly and time-consuming. Although non-implantable neuromodulation (NIN) techniques such as transcranial magnetic stimulation, transcranial direct current stimulation, electroconvulsive therapy, and magnetic seizure therapy are gaining momentum for treating MDD, the efficacy of non-convulsive techniques is still modest, whereas use of convulsive modalities is limited by their cognitive side effects. In this context, we propose that NIN techniques could benefit from a precision-oriented approach. In this review, we discuss the challenges and opportunities in implementing such a framework, focusing on enhancing NIN effects via a combination of individualized cognitive interventions, using closed-loop approaches, identifying multimodal biomarkers, using computer electric field modeling to guide targeting and quantify dosage, and using machine learning algorithms to integrate data collected at multiple biological levels and identify clinical responders. Though promising, this framework is currently limited, as previous studies have employed small samples and did not sufficiently explore pathophysiological mechanisms associated with NIN response and side effects. Moreover, cost-effectiveness analyses have not been performed. Nevertheless, further advancements in clinical trials of NIN could shift the field toward a more "precision-oriented" practice.

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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.

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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.

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Background: The Maslach Burnout Inventory-Human Services Survey (MBI-HSS) is the most commonly used instrument to assess burnout. Although various factors have been reported to influence its validity, the influence of major depressive disorder (MDD) has not been previously considered. We developed this study to investigate the influence of MDD on the psychometric properties of the MBI-HSS in nursing assistants. Results: From a sample of 521 nursing assistants, we found in those with MDD (n = 138, 24.56%) a degree of data misfit into the model, revealed by non-acceptable values for the root mean square error of approximation (RMSEA; 0.073; p = 0.004) and for the comparative fit index (CFI; 0.912), while in the non-MDD group these indices were acceptable and good, respectively, for RMSEA (0.048; p = 0.639) and for CFI (0.951). Also, we found higher coefficients of correlation among MBI-HSS factors and less items loading properly in their respective factors in the MDD subset, when compared to the non-MDD subset. For the total sample, while original 3-factor solution was an acceptable model, the bifactor model fitted data better. Conclusions: MDD may impair the construct validity of MBI-HSS subscales, by increasing measurement error and decreasing model fitness. Therefore, researchers and health professionals should be aware of potential changes in the psychometric properties of the MBI-HSS when applied in subjects with depression.

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BACKGROUND: Patients with major depressive disorder (MDD) have distinct personality traits, compared with control subjects, although the role of anxiety and positive and negative affects in this finding is unclear. DESIGN AND SETTING: A case-control study enrolling 103 antidepressant-free depressed patients and 103 age and gender-matched controls was conducted at the University Hospital, University of São Paulo. METHODS: The self-reported scales of the Positive and Negative Affect Schedule (PANAS), State-Trait Anxiety Inventory (STAI) and Cloninger's Temperament and Character Inventory (TCI) were applied. Temperament and character traits were compared between groups using multivariate and bivariate analyses of variance (MANOVA and ANOVA). The influence of anxiety and affect was further investigated using ANOVA and mediation analyses. RESULTS: Depressed patients presented higher harm avoidance and lower self-directedness scores than controls. After adjustment for anxiety trait, harm avoidance was no longer significantly different between groups. Mediation analysis revealed that the anxiety trait, but not state-anxiety or affect, fully mediated the influence of group (depressed versus control subjects) on harm avoidance. CONCLUSIONS: Our findings confirm that depressed patients present personality traits distinct from those of controls and suggest that MDD is not directly associated with harm avoidance, but that this effect is fully mediated through the anxiety trait.

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OBJECTIVES: We developed this study to investigate the association of fibromyalgia with personality traits, controlling for depression and other potential confounders. METHODS: We assessed personality traits using the Cloninger's Temperament and Character Inventory (TCI) in 78 female patients with fibromyalgia and in a control group of 78 subjects without fibromyalgia. The Mini-International Neuropsychiatric Interview was used to assess depression and anxiety diagnoses. To investigate the association between fibromyalgia and the Cloninger's Temperament and Character Inventory we performed unadjusted and adjusted analyses of covariance, using the TCI score as dependent variable and adjusting the model for depression, anxiety and for clinical and socio-demographic variables. We used a backward selection method to choose the final model. RESULTS: In the unadjusted analysis, fibromyalgia was associated with all personality traits, except persistency. After adjusting for depression and anxiety, patients with fibromyalgia presented decreased novelty seeking compared to controls; the differences in other personality traits were no longer significant. Novelty seeking was also correlated with the length of history of fibromyalgia and pain intensity. CONCLUSIONS: Decreased novelty seeking may be a personality trait associated with fibromyalgia. Depression and anxiety should be considered potential confounders in the evaluation of personality traits in this population.

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BACKGROUND: Major depressive disorder (MDD) is associated with impairments in nonverbal behaviors (NVBs) and vagal activity. The polyvagal theory proposes that vagal activity regulates heart rate and NVBs by modulating a common anatomically and neurophysiologically discrete social engagement system. However, the association between these putative endophenotypes has not yet been explored. We hypothesize that in MDD, NVBs indicating positive affects and social interest and those indicating negative feelings and social disinterest could be associated with different patterns of vagal activity. METHODS: For this cross-sectional study we recruited 50 antidepressant-free participants with moderate-to-severe MDD. Vagal activity was indexed by heart rate variability (HRV) measures, and positive and negative nonverbal behaviors (NVBs) by a validated ethogram. Associations between NVBs and HRV were explored by bivariate analyses and multivariable models were adjusted by age, gender, depression severity, and self-reported positive and negative affects. RESULTS: HRV measures indicative of higher vagal activity were positively correlated with positive NVBs exhibited during the clinical interview. Conversely, NVBs related to negative affects, low energy and social disinterest were not associated with HRV. LIMITATIONS: Absence of a control group. CONCLUSIONS: The findings highlight that the examined depression endophenotypes (nonverbal behaviors and vagal activity) are related, shedding light on MDD pathophysiology in the context of the polyvagal theory.

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OBJECTIVE: Debate has focused on the effects of the selective serotonin reuptake inhibitor (SSRI) antidepressants on heart rate (HR) and HR variability (HRV), both of which are predictors of adverse cardiovascular events. Here, we examine the associations between specific SSRI antidepressants and resting state HR (and HRV) after accounting for a host of potential confounding factors using propensity score techniques. METHODS: Participants included 10,466 not taking antidepressants, 46 participants taking escitalopram, 86 taking citalopram, 66 taking fluoxetine, 103 taking paroxetine, and 139 taking sertraline. HR and HRV (root mean square of successive squared differences, high frequency) were extracted from 10-minute resting-state ECGs. Analyses including propensity score weighting and matching were conducted using R-statistics to control for potentially confounding variables. RESULTS: Major findings indicated that users of all SSRI medications-except fluoxetine-displayed lower HRV relative to nonusers. Users of paroxetine also displayed significantly lower HRV relative to users of citalopram (Cohen's d = 0.42), fluoxetine (Cohen's d = 0.54), and sertraline (Cohen's d = 0.35), but not escitalopram. Although associations were also observed for HR, these were less robust than those for HRV. CONCLUSIONS: Although paroxetine is associated with decreases in HRV relative to nonusers, as well as users of other SSRI medications, fluoxetine was the only medication not to display significant alterations in HR or HRV. These conclusions are limited by the cross-sectional design and nonrandomized nature of medication prescriptions. Findings highlight the importance of focusing on specific medications, rather than more heterogeneous groupings according to antidepressant action, and may have implications for health and well-being for the longer term.

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

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

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

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