Takotsubo cardiomyopathy secondary to electroconvulsive therapy in a young adult with Down syndrome regression disorder.

We report the case of an 18-year-old woman with Down syndrome (DS) who developed Takotsubo cardiomyopathy (TSC) immediately after the administration of electroconvulsive therapy (ECT), a treatment prescribed for Down syndrome regression disorder resistant to oral psychotropic drugs. TSC is a nonischemic cardiomyopathy related to psychological or physical stress, which has been described as a rare complication of ECT (Kinoshita et al., 2023, Journal of Electroconvulsive Therapy, 39, 185-192). The clinical description of the case is accompanied by a discussion of the peculiarities of the autonomic nervous system in DS.

Asociación bidireccional entre uso de tabaco y riesgo de depresión en el estudio de cohorte SUN / Bidirectional association between tobacco use and depression risk in the SUN cohort study

Evaluamos la asociación del consumo de tabaco o su abandono con el riesgo de depresión y determinamos si presentar depresión se asoció al inicio de fumar. Diseño: estudio de cohortes prospectivo de 16.519 graduados universitarios españoles sin depresión al inicio del estudio. El consumo de tabaco se determinó al inicio y tras cuatro años de seguimiento. Los casos incidentes de depresión fueron autoinformados en los cuestionarios de seguimiento. Usamos modelos de regresión de Cox para estimar los Hazard Ratios (HR) de depresión según el nivel de tabaquismo inicial y sus cambios. Se estimaron los Odds Ratios (OR) para la asociación entre prevalencia de tabaquismo a lo largo de la vida y comienzo del hábito con modelos de regresión logística. Se observó un HR (IC 95%) para fumadores de 1,24 (1,05-1,46) en comparación con los que nunca habían fumado. Los participantes con la exposición más alta al tabaco (≥ 20 paquetes-año) tuvieron un incremento relativo del riesgo de depresión de 38%. Dejar de fumar durante los primeros cuatro años de seguimiento se asoció inversamente con la depresión (HR = 0,63; IC 95% = 0,40-0,99). Observamos un incremento significativo del riesgo de aparición de tabaquismo en los participantes con prevalencia de depresión a lo largo de la vida (OR multivariable = 1,44; IC 95% = 1,13-1,83). Encontramos una asociación bidireccional entre el consumo de tabaco y la depresión en la cohorte SUN. El control del tabaco y las campañas sanitarias de abstinencia deberían considerarse estrategias efectivas de salud pública para prevenir y manejar los trastornos depresivos. (AU)

We assessed the association of tobacco use or smoking cessation with depression risk and determined if the presence of a depressive disorder was associated with smoking onset. We conducted a prospective cohort study (SUN Project) based on 16,519 Spanish university graduates without depression at baseline. Tobacco use was determined at baseline and after four years of follow-up. Incident cases of depression were ascertained according to a previously validated report of a clinical diagnosis of depression during follow-up. Multivariable Cox regression models were used to estimate hazard ratios (HR) of depression according to previous smoking status. We used logistic regression models as a secondary analysis to estimate Odds Ratios (OR) of smoking onset during the first four years of follow-up according to lifetime depression prevalence at baseline. The multivariable HR (95% CI) for current smokers was 1.24 (1.05-1.46) as compared to participants who had never smoked. Participants with the highest exposure to tobacco (≥ 20 packsyears) had a significant 38% relative increment in depression risk. Smoking cessation during the first four years of follow-up was inversely associated with depression (HR = 0.63; 95% CI = 0.40-0.99). Finally, a significant increment in the risk of smoking onset for participants with lifetime depression prevalence was observed (multivariable OR = 1.44; 95% CI = 1.13-1.83). A bidirectional association between tobacco use and depression in the SUN cohort was found. Therefore, tobacco control and health promotion campaigns for smoking cessation could be considered as effective strategies of public health for the prevention and management of depressive disorders. (AU)

Mediterranean diet-based intervention to improve depressive symptoms: analysis of the PREDIDEP randomized trial.

BACKGROUND: The effect of an intervention based on Mediterranean diet on reducing recurrence risk or subsyndromal depressive symptoms in recovered depressed patients has not been explored. METHODS: The PREDIDEP study was a two-year randomized trial designed to assess the effect of the Mediterranean Diet enriched with extra virgin olive oil on depression recurrence. At baseline and at four, eight, 16, 20, and 24 months of follow-up, depressive symptoms were evaluated through the Beck Depression inventory. Cox regression analysis was fitted to assess the role of dietary intervention on the risk of depression recurrence. Mixed effects linear models were used to assess changes in depressive subsyndromal symptoms according to the intervention. RESULTS: After two years of intervention, the dietary intervention group (n = 103) compared to the control group (n = 93) showed no differences regarding depression recurrence risk as main outcome. As secondary outcomes, an improvement of depressive symptoms was yielded at four (-2.15; 95% CI = -4.00 to -0.29) and eight months (-2.42; 95% CI = -4.17 to -0.67) in the intervention group, with no changes in control group. Moreover, at 20 months, significant differences were found between groups (-3.35; 95% CI = -6.08 to -0.61). CONCLUSIONS: An intervention with Mediterranean diet in patients with previous depressive episodes might contribute to the reduction of depressive subsyndromal symptoms.

COVID-19 risk, course and outcome in people with mental disorders: a systematic review and meta-analyses.

AIMS: It has been suggested that people with mental disorders have an elevated risk to acquire severe acute respiratory syndrome coronavirus 2 and to be disproportionally affected by coronavirus disease 19 (COVID-19) once infected. We aimed to analyse the COVID-19 infection rate, course and outcome, including mortality and long COVID, in people with anxiety, depressive, neurodevelopmental, schizophrenia spectrum and substance use disorders relative to control subjects without these disorders. METHODS: This study constitutes a preregistered systematic review and random-effects frequentist and Bayesian meta-analyses. Major databases were searched up until 27 June 2023. RESULTS: Eighty-one original articles were included reporting 304 cross-sectional and prospective effect size estimates (median n per effect-size = 114837) regarding associations of interest. Infection risk was not significantly increased for any mental disorder that we investigated relative to samples of people without these disorders. The course of COVID-19, however, is relatively severe, and long COVID and COVID-19-related hospitalization are more likely in all patient samples that we investigated. The odds of dying from COVID-19 were high in people with most types of mental disorders, except for those with anxiety and neurodevelopmental disorders relative to non-patient samples (pooled ORs range, 1.26-2.57). Bayesian analyses confirmed the findings from the frequentist approach and complemented them with estimates of the strength of evidence. CONCLUSIONS: Once infected, people with pre-existing mental disorders are at an elevated risk for a severe COVID-19 course and outcome, including long COVID and mortality, relative to people without pre-existing mental disorders, despite an infection risk not significantly increased.

Time discrimination and change detection could share a common brain network: findings of a task-based fMRI study.

Introduction: Over the past few years, several studies have described the brain activation pattern related to both time discrimination (TD) and change detection processes. We hypothesize that both processes share a common brain network which may play a significant role in more complex cognitive processes. The main goal of this proof-of-concept study is to describe the pattern of brain activity involved in TD and oddball detection (OD) paradigms, and in processes requiring higher cognitive effort. Methods: We designed an experimental task, including an auditory test tool to assess TD and OD paradigms, which was conducted under functional magnetic resonance imaging (fMRI) in 14 healthy participants. We added a cognitive control component into both paradigms in our test tool. We used the general linear model (GLM) to analyze the individual fMRI data images and the random effects model for group inference. Results: We defined the areas of brain activation related to TD and OD paradigms. We performed a conjunction analysis of contrast TD (task > control) and OD (task > control) patterns, finding both similarities and significant differences between them. Discussion: We conclude that change detection and other cognitive processes requiring an increase in cognitive effort require participation of overlapping functional and neuroanatomical components, suggesting the presence of a common time and change detection network. This is of particular relevance for future research on normal cognitive functioning in the healthy population, as well as for the study of cognitive impairment and clinical manifestations associated with various neuropsychiatric conditions such as schizophrenia.

Effects of esketamine on patient-reported outcomes in major depressive disorder with active suicidal ideation and intent: a pooled analysis of two randomized phase 3 trials (ASPIRE I and ASPIRE II).

PURPOSE: To assess the effect of esketamine nasal spray on patient-reported outcomes (PROs) in patients with major depressive disorder having active suicidal ideation with intent (MDSI). METHODS: Patient-level data from two phase 3 studies (ASPIRE I; ASPIRE II) of esketamine + standard of care (SOC) in patients (aged 18-64 years) with MDSI, were pooled. PROs were evaluated from baseline through end of the double-blind treatment phase (day 25). Outcome assessments included: Beck Hopelessness Scale (BHS), Quality of Life (QoL) in Depression Scale (QLDS), European QoL Group-5-Dimension-5-Level (EQ-5D-5L), and 9-item Treatment Satisfaction Questionnaire for Medication (TSQM-9). Changes in BHS and QLDS scores (baseline to day 25) were analyzed using a mixed-effects model for repeated measures (MMRM). RESULTS: Pooled data for esketamine + SOC (n = 226; mean age: 40.5 years, 59.3% females) and placebo + SOC (n = 225; mean age: 39.6 years, 62.2% females) were analyzed. Mean ± SD change from baseline to day 25, esketamine + SOC vs placebo + SOC (least-square mean difference [95% CI] based on MMRM): BHS total score, - 7.4 ± 6.7 vs - 6.8 ± 6.5 [- 1.0 (- 2.23, 0.21)]; QLDS score, - 14.4 ± 11.5 vs - 12.2 ± 10.8 [- 3.1 (- 5.21, - 1.02)]. Relative risk (95% CI) of reporting perceived problems (slight to extreme) in EQ-5D-5L dimensions (day 25) in esketamine + SOC vs placebo + SOC: mobility [0.78 (0.50, 1.20)], self-care [0.83 (0.55, 1.27)], usual activities [0.87 (0.72, 1.05)], pain/discomfort [0.85 (0.69, 1.04)], and anxiety/depression [0.90 (0.80, 1.00)]. Mean ± SD changes from baseline in esketamine + SOC vs placebo + SOC for health status index: 0.23 ± 0.21 vs 0.19 ± 0.22; and for EQ-Visual Analogue Scale: 24.0 ± 27.2 vs 19.3 ± 24.4. At day 25, mean ± SD in domains of TSQM-9 scores in esketamine + SOC vs placebo + SOC were: effectiveness, 67.2 ± 25.3 vs 56.2 ± 26.8; global satisfaction, 69.9 ± 25.2 vs 56.3 ± 27.8; and convenience, 74.0 ± 19.4 vs 75.4 ± 18.7. CONCLUSION: These PRO data support the patient perspective of the effect associated with esketamine + SOC in improving health-related QoL in patients with MDSI. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: ASPIRE I, NCT03039192 (Registration date: February 1, 2017); ASPIRE II, NCT03097133 (Registration date: March 31, 2017).

Cigarette smoking and risk of suicide in bipolar disorder: a systematic review.

Objective: Bipolar disorder (BD) is a highly prevalent, chronic and recurrent mental illness. The smoking rates in patients with BD are much higher than those of the general population, and BD is associated with an increased risk of suicide. An association between smoking and suicidal behavior has been found in the general population, this systematic review examines whether there is evidence of an association between smoking and suicide behavior in patients with BD. Method: A database search was carried out in Medline, Embase, The Cochrane Library, Scopus, and Web of Science, updated until December 31st, 2021, according to the 2020 PRISMA guidelines. We identified prospective and retrospective studies that included patients diagnosed with BD types I, II, and not otherwise specified, and in which smoking and suicidal behavior were correlated. Articles that focused exclusively on other mental disorders were excluded. The Ottawa-Newcastle scale was used to assess the methodological quality of the included articles. Results: Fifteen articles (n = 7,395) met all the inclusion criteria. In nine of these articles, the authors found an association between smoking and suicidal behavior in BD, while in the remaining six articles, this association was not found. A great deal of variability was observed between articles, particularly in the measurement of suicidal behavior and tobacco consumption. The risk of bias, as assessed by the NOS, was high for most of the included articles, except for two papers, whose risk was low. Conclusion: It was not possible to establish a clear relationship between tobacco use and the risk of suicide in BD patients due to the heterogeneity of the articles included in this systematic review, which had different sample sizes and methodological issues. However, both conditions are highly prevalent and have a negative impact on the prognosis of BD. Therefore, a systematic approach is needed, based on accurate measurement of a patient's smoking habits and their risk of suicidal behavior, in order to establish an appropriate therapeutic plan. Additional information: This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors and was registered on PROSPERO with the CRD42022301570 on January 21th 2022.

SARS-CoV-2 susceptibility and COVID-19 illness course and outcome in people with pre-existing neurodegenerative disorders: systematic review with frequentist and Bayesian meta-analyses.

BACKGROUND: People with neurodegenerative disease and mild cognitive impairment (MCI) may have an elevated risk of acquiring severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and may be disproportionally affected by coronavirus disease 2019 (COVID-19) once infected. AIMS: To review all eligible studies and quantify the strength of associations between various pre-existing neurodegenerative disorders and both SARS-CoV-2 susceptibility and COVID-19 illness course and outcome. METHOD: Pre-registered systematic review with frequentist and Bayesian meta-analyses. Systematic searches were executed in PubMed, Web of Science and preprint servers. The final search date was 9 January 2023. Odds ratios (ORs) were used as measures of effect. RESULTS: In total, 136 primary studies (total sample size n = 97 643 494), reporting on 268 effect-size estimates, met the inclusion criteria. The odds for a positive SARS-CoV-2 test result were increased for people with pre-existing dementia (OR = 1.83, 95% CI 1.16-2.87), Alzheimer's disease (OR = 2.86, 95% CI 1.44-5.66) and Parkinson's disease (OR = 1.65, 95% CI 1.34-2.04). People with pre-existing dementia were more likely to experience a relatively severe COVID-19 course, once infected (OR = 1.43, 95% CI 1.00-2.03). People with pre-existing dementia or Alzheimer's disease were at increased risk for COVID-19-related hospital admission (pooled OR range: 1.60-3.72). Intensive care unit admission rates were relatively low for people with dementia (OR = 0.54, 95% CI 0.40-0.74). All neurodegenerative disorders, including MCI, were at higher risk for COVID-19-related mortality (pooled OR range: 1.56-2.27). CONCLUSIONS: Our findings confirm that, in general, people with neurodegenerative disease and MCI are at a disproportionally high risk of contracting COVID-19 and have a poor outcome once infected.

Effect of a dietary intervention based on the Mediterranean diet on the quality of life of patients recovered from depression: Analysis of the PREDIDEP randomized trial.

INTRODUCTION: There is substantial evidence supporting that improving diet quality leads to improved health-related quality of life (HRQoL). Our major aim was to assess the effectiveness of a Mediterranean diet-based nutritional intervention to improve HRQoL in the context of a secondary prevention trial of depression. Secondarily to assess its effectiveness among adults aged 60 or more years. METHODS: The PREDIDEP study is a 2-year multicentre, randomized, single-blinded nutritional trial. At baseline and at 1-year and 2-year follow-up, SF-36 health survey questionnaire was collected to evaluate participants' HRQoL (total and specific range for each of the 8 dimensions: 0 to 100 points). Mixed effect linear models were used to assess changes in HRQoL according to adherence to the Mediterranean diet. The trial was registered at ClinicalTrials.govNCT03081065. RESULTS: After 2 years of intervention, the Mediterranean Diet intervention group compared to control group (without nutritional intervention, only usual clinical care) showed an improvement in some dimensions of HRQoL such as Mental Health (7.22; 95 % CI = 2.22-12.22) (between-group difference: 6.79; 95 % CI -0.14-13.73, p = 0.055); Vitality (9.51; 95 % CI = 4.00-15.03) (between-group difference: 9.00; 95 % CI 1.75-16.25, p = 0.020); Mental Summary Component (2.83; 95 % CI = 0.55-5.11) (between-group difference: 1.17; 95 % CI = -1.96-4.30, p = 0.462); and General Health (10.70; 95 % CI = 5.58-15.81) (between-group difference: 6.20; 95 % CI = -0.89-13.28, p = 0.086). Similar results were observed for participants aged 60 or more years. CONCLUSION: The intervention based on Mediterranean diet in patients with previous depression seems to be effective in improving HRQoL, especially the mental dimensions. This effect is also observed among participants aged 60 or more years.

Differential malondialdehyde (MDA) detection in plasma samples of patients with major depressive disorder (MDD): A potential biomarker.

OBJECTIVE: To measure plasma levels of malondialdehyde (MDA), a marker of oxidative stress (OS), in patients with major depressive disorder (MDD) compared with healthy control (HC) subjects in order to determine if it is a possible biomarker of depression. METHODS: This prospective cross-sectional study enrolled patients with MDD and HC subjects. The plasma levels of MDA were measured using a commercially-available colorimetric assay. RESULTS: A total of 30 patients with MDD and 20 HC subjects with similar sex, age and body mass index distribution were enrolled in the study. Patients with MDD had significantly higher plasma levels of MDA than the HC subjects. Receiver operating characteristic curve analysis for plasma MDA levels in patients with MDD demonstrated an area under the curve of 0.9767. CONCLUSION: The findings of this current study provide further evidence of the role pathophysiological relevance of OS and MDA in MDD. This study provides the basis for the use of MDA as a biomarker for MDD.

Bidirectional association between tobacco use and depression risk in the SUN cohort study. / Asociación bidireccional entre uso de tabaco y riesgo de depresión en el estudio de cohorte SUN.

We assessed the association of tobacco use or smoking cessation with depression risk and determined if the presence of a depressive disorder was associated with smoking onset. We conducted a prospective cohort study (SUN Project) based on 16,519 Spanish university graduates without depression at baseline. Tobacco use was determined at baseline and after four years of follow-up. Incident cases of depression were ascertained according to a previously validated report of a clinical diagnosis of depression during follow-up. Multivariable Cox regression models were used to estimate hazard ratios (HR) of depression according to previous smoking status. We used logistic regression models as a secondary analysis to estimate Odds Ratios (OR) of smoking onset during the first four years of follow-up according to lifetime depression prevalence at baseline. The multivariable HR (95% CI) for current smokers was 1.24 (1.05-1.46) as compared to participants who had never smoked. Participants with the highest exposure to tobacco (≥ 20 packs-years) had a significant 38% relative increment in depression risk. Smoking cessation during the first four years of follow-up was inversely associated with depression (HR = 0.63; 95% CI = 0.40-0.99). Finally, a significant increment in the risk of smoking onset for participants with lifetime depression prevalence was observed (multivariable OR = 1.44; 95% CI = 1.13-1.83). A bidirectional association between tobacco use and depression in the SUN cohort was found. Therefore, tobacco control and health promotion campaigns for smoking cessation could be considered as effective strategies of public health for the prevention and management of depressive disorders.

Evaluamos la asociación del consumo de tabaco o su abandono con el riesgo de depresión y determinamos si presentar depresión se asoció al inicio de fumar. Diseño: estudio de cohortes prospectivo de 16.519 graduados universitarios españoles sin depresión al inicio del estudio. El consumo de tabaco se determinó al inicio y tras cuatro años de seguimiento. Los casos incidentes de depresión fueron autoinformados en los cuestionarios de seguimiento. Usamos modelos de regresión de Cox para estimar los Hazard Ratios (HR) de depresión según el nivel de tabaquismo inicial y sus cambios. Se estimaron los Odds Ratios (OR) para la asociación entre prevalencia de tabaquismo a lo largo de la vida y comienzo del hábito con modelos de regresión logística. Se observó un HR (IC 95%) para fumadores de 1,24 (1,05-1,46) en comparación con los que nunca habían fumado. Los participantes con la exposición más alta al tabaco (≥ 20 paquetes-año) tuvieron un incremento relativo del riesgo de depresión de 38%. Dejar de fumar durante los primeros cuatro años de seguimiento se asoció inversamente con la depresión (HR = 0,63; IC 95% = 0,40-0,99). Observamos un incremento significativo del riesgo de aparición de tabaquismo en los participantes con prevalencia de depresión a lo largo de la vida (OR multivariable = 1,44; IC 95% = 1,13-1,83). Encontramos una asociación bidireccional entre el consumo de tabaco y la depresión en la cohorte SUN. El control del tabaco y las campañas sanitarias de abstinencia deberían considerarse estrategias efectivas de salud pública para prevenir y manejar los trastornos depresivos.

An fMRI Study Using a Combined Task of Interval Discrimination and Oddball Could Reveal Common Brain Circuits of Cognitive Change.

Recent functional neuroimaging studies suggest that the brain networks responsible for time processing are involved during other cognitive processes, leading to a hypothesis that time-related processing is needed to perform a range of tasks across various cognitive functions. To examine this hypothesis, we analyze whether, in healthy subjects, the brain structures activated or deactivated during performance of timing and oddball-detection type tasks coincide. To this end, we conducted two independent signed differential mapping (SDM) meta-analyses of functional magnetic resonance imaging (fMRI) studies assessing the cerebral generators of the responses elicited by tasks based on timing and oddball-detection paradigms. Finally, we undertook a multimodal meta-analysis to detect brain regions common to the findings of the two previous meta-analyses. We found that healthy subjects showed significant activation in cortical areas related to timing and salience networks. The patterns of activation and deactivation corresponding to each task type partially coincided. We hypothesize that there exists a time and change-detection network that serves as a common underlying resource used in a broad range of cognitive processes.

Impact of review method on the conclusions of clinical reviews: A systematic review on dietary interventions in depression as a case in point.

BACKGROUND: The recommendations of experts who write review articles are a critical determinant of the adaptation of new treatments by clinicians. Several types of reviews exist (narrative, systematic, meta-analytic), and some of these are more vulnerable to researcher bias than others. Recently, the interest in nutritional interventions in psychiatry has increased and many experts, who are often active researchers on this topic, have come to strong conclusions about the benefits of a healthy diet on depression. In a young and active field of study, we aimed to investigate whether the strength of an author's conclusion is associated with the type of review article they wrote. METHODS: Systematic searches were performed in PubMed, Web of Science, Cochrane Database of Systematic Reviews, and Google Scholar for narrative reviews and systematic reviews with and without meta-analyses on the effects of diet on depression (final search date: May 30th, 2020). Conclusions were extracted from the abstract and discussion section and rated as strong, moderate, or weak by independent raters who were blind to study type. A benchmark on legitimate conclusion strength was based on a GRADE assessment of the highest level of evidence. This systematic review was registered with PROSPERO, number CRD42020141372. FINDINGS: 24 narrative reviews, 12 systematic reviews, and 14 meta-analyses were included. In the abstract, 33% of narrative reviews and 8% of systematic reviews came to strong conclusions, whereas no meta-analysis did. Narrative reviews were 8.94 (95% CI: 2.17, 36.84) times more likely to report stronger conclusions in the abstract than systematic reviews with and without meta-analyses. These findings were similar for conclusions in the discussion section. Narrative reviews used 45.6% fewer input studies and were more likely to be written by authors with potential conflicts of interest. A study limitation is the subjective nature of the conclusion classification system despite high inter-rater agreements and its confirmation outside of the review team. CONCLUSIONS: We have shown that narrative reviews come to stronger conclusions about the benefits of a healthy diet on depression despite inconclusive evidence. This finding empirically underscores the importance of a systematic method for summarizing the evidence of a field of study. Journal editors may want to reconsider publishing narrative reviews before meta-analytic reviews are available.

Dimensions of leisure-time physical activity and risk of depression in the "Seguimiento Universidad de Navarra" (SUN) prospective cohort.

BACKGROUND: An inverse association between total leisure-time physical activity (LTPA) and depression has been previously documented in the scientific literature. Our objective was to prospectively assess the association of LTPA with the risk of depression, focusing on several dimensions of LTPA (intensity, duration and type). METHODS: The SUN (Seguimiento Universidad de Navarra) project is a prospective cohort study formed by Spanish university graduates. A total of 15,488 adults (40.2% men, mean age 37 ± 12 years) initially free of depression were assessed. A report of a validated medical diagnosis of depression or the habitual use of antidepressants (any of both) were considered as incident cases of depression. LTPA was estimated through previously validated self-reported questionnaires. Participants were classified following Physical Activity recommendations from the World Health Organization, and according to the intensity, duration and type of LTPA. Cox proportional hazards regression models were run, adjusted for demographic, lifestyle, and dietary factors, to estimate adjusted hazard ratios (HR) of depression and 95% confidence intervals (CI). RESULTS: During 163,059 person-years of follow-up we registered 870 incident cases of depression. Participants with higher total LTPA (METs-h/wk) and higher duration of LTPA (hours/wk) exhibited a lower risk of depression HR = 0.84 (95% CI: 0.72-0.99) and HR = 0.83 (0.70-0.99) respectively, whereas intensity of LTPA (MET) did not show any association with depression. CONCLUSION: Participants with higher LTPA had a lower risk of depression. The inverse association was stronger for total LPTA time than for its intensity. Higher duration of LTPA should be encouraged to prevent depression.

Correction to: Dimensions of leisure-time physical activity and risk of depression in the "Seguimiento Universidad de Navarra" (SUN) prospective cohort.

After publication of our article [1] we have been notified that Table 2 was incorrectly formatted.

Blunted Expansion of Regulatory T Lymphocytes Is Associated With Increased Bacterial Translocation in Patients With Major Depressive Disorder.

Background: Major Depressive Disorder (MDD) is associated with both proinflammatory and adaptive immune response abnormalities. Regulatory T lymphocytes (Tregs), a subtype of CD4+ T cells, are relevant for maintaining immune-inflammatory system homeostasis and control of inflammation such as the kind potentially induced by the interactions between the intestinal microbiome and gut mucosa. We investigated the Treg population and its distribution along their stages of differentiation/activation, as well as its function in MDD patients without concomitant diseases. We also studied the potential association between Treg alterations, intestinal barrier damage, and bacterial translocation. Methods: 30 MDD patients and 20 healthy controls were studied. The levels of circulating CD25FoxP3+ Tregs and their distribution on the naïve (TN), effector (TE), central (TCM), and effector memory(TEM) differentiation/activation stages were analyzed using polychromatic flow cytometry. Chemokine receptors (CCR) 2, 5, and 6, and the intracytoplasmic IL-10 expression by the Tregs were also analyzed. The serum IL-10 was measured using Luminex. The serum levels of zonulin and the intestinal fatty acid-binding protein (I-FABP), both markers of gut barrier function, and the LPS-binding protein (LBP), a marker of bacterial translocation, were measured using an enzyme-linked immunosorbent assay. Results: MDD patients had increased number of circulating Tregs cells with enhanced number of Tregs at the TN, TE, TCM, and TEM stages. The percentage of Tregs cells at TN stage was significantly higher in MDD patients. The percentage of Tregs that expressed CCR2 and CCR6 was increased as well as those expressing IL-10. MDD patients had significantly increased levels of circulating I-FABP and LBP. MDD patients with high LBP levels had a significant reduction in the number of circulating Tregs compared to normal-LBP MDD patients. Conclusions: MDD patients showed an expansion of circulating Tregs and their CD25highFoxP3+ and CD25lowFoxP3+ subsets throughout the different stages of CD4+ T lymphocyte differentiation/activation. Tregs also showed an increased frequency of cells expressing CCR6 and CCR2. IL-10 Treg production was also enhanced in MDD patients that concurrently had increased serum IL-10 levels. However, this Treg expansion was blunted in MDD patients with gut barrier damage and increased bacterial translocation.

Efficacy of Esketamine Nasal Spray Plus Oral Antidepressant Treatment for Relapse Prevention in Patients With Treatment-Resistant Depression: A Randomized Clinical Trial.

Importance: Controlled studies have shown short-term efficacy of esketamine for treatment-resistant depression (TRD), but long-term effects remain to be established. Objective: To assess the efficacy of esketamine nasal spray plus an oral antidepressant compared with an oral antidepressant plus placebo nasal spray in delaying relapse of depressive symptoms in patients with TRD in stable remission after an induction and optimization course of esketamine nasal spray plus an oral antidepressant. Design, Setting, and Participants: In this phase 3, multicenter, double-blind, randomized withdrawal study conducted from October 6, 2015, to February 15, 2018, at outpatient referral centers, 705 adults with prospectively confirmed TRD were enrolled; 455 entered the optimization phase and were treated with esketamine nasal spray (56 or 84 mg) plus an oral antidepressant. After 16 weeks of esketamine treatment, 297 who achieved stable remission or stable response entered the randomized withdrawal phase. Interventions: Patients who achieved stable remission and those who achieved stable response (without remission) were randomized 1:1 to continue esketamine nasal spray or discontinue esketamine treatment and switch to placebo nasal spray, with oral antidepressant treatment continued in each group. Main Outcomes and Measures: Time to relapse was examined in patients who achieved stable remission, as assessed using a weighted combination log-rank test. Results: Among the 297 adults (mean age [SD], 46.3 [11.13] years; 197 [66.3%] female) who entered the randomized maintenance phase, 176 achieved stable remission; 24 (26.7%) in the esketamine and antidepressant group and 39 (45.3%) in the antidepressant and placebo group experienced relapse (log-rank P = .003, number needed to treat [NNT], 6). Among the 121 who achieved stable response, 16 (25.8%) in the esketamine and antidepressant group and 34 (57.6%) in the antidepressant and placebo group experienced relapse (log-rank P < .001, NNT, 4). Esketamine and antidepressant treatment decreased the risk of relapse by 51% (hazard ratio [HR], 0.49; 95% CI, 0.29-0.84) among patients who achieved stable remission and 70% (HR, 0.30; 95% CI, 0.16-0.55) among those who achieved stable response compared with antidepressant and placebo treatment. The most common adverse events reported for esketamine-treated patients after randomization were transient dysgeusia, vertigo, dissociation, somnolence, and dizziness (incidence, 20.4%-27.0%), each reported in fewer patients (<7%) treated with an antidepressant and placebo. Conclusions and Relevance: For patients with TRD who experienced remission or response after esketamine treatment, continuation of esketamine nasal spray in addition to oral antidepressant treatment resulted in clinically meaningful superiority in delaying relapse compared with antidepressant plus placebo. Trial Registration: ClinicalTrials.gov identifier: NCT02493868.

Efficacy and Safety of Flexibly Dosed Esketamine Nasal Spray Combined With a Newly Initiated Oral Antidepressant in Treatment-Resistant Depression: A Randomized Double-Blind Active-Controlled Study.

OBJECTIVE: About one-third of patients with depression fail to achieve remission despite treatment with multiple antidepressants. This study compared the efficacy and safety of switching patients with treatment-resistant depression from an ineffective antidepressant to flexibly dosed esketamine nasal spray plus a newly initiated antidepressant or to a newly initiated antidepressant (active comparator) plus placebo nasal spray. METHODS: This was a phase 3, double-blind, active-controlled, multicenter study conducted at 39 outpatient referral centers. The study enrolled adults with moderate to severe nonpsychotic depression and a history of nonresponse to at least two antidepressants in the current episode, with one antidepressant assessed prospectively. Confirmed nonresponders were randomly assigned to treatment with esketamine nasal spray (56 or 84 mg twice weekly) and an antidepressant or antidepressant and placebo nasal spray. The primary efficacy endpoint, change from baseline to day 28 in Montgomery-Åsberg Depression Rating Scale (MADRS) score, was assessed by a mixed-effects model using repeated measures. RESULTS: Of 435 patients screened, 227 underwent randomization and 197 completed the 28-day double-blind treatment phase. Change in MADRS score with esketamine plus antidepressant was significantly greater than with antidepressant plus placebo at day 28 (difference of least square means=-4.0, SE=1.69, 95% CI=-7.31, -0.64); likewise, clinically meaningful improvement was observed in the esketamine plus antidepressant arm at earlier time points. The five most common adverse events (dissociation, nausea, vertigo, dysgeusia, and dizziness) all were observed more frequently in the esketamine plus antidepressant arm than in the antidepressant plus placebo arm; 7% and 0.9% of patients in the respective treatment groups discontinued study drug because of an adverse event. Adverse events in the esketamine plus antidepressant arm generally appeared shortly after dosing and resolved by 1.5 hours after dosing. CONCLUSIONS: Current treatment options for treatment-resistant depression have considerable limitations in terms of efficacy and patient acceptability. Esketamine is expected to address an unmet medical need in this population through its novel mechanism of action and rapid onset of antidepressant efficacy. The study supports the efficacy and safety of esketamine nasal spray as a rapidly acting antidepressant for patients with treatment-resistant depression.

Use of non-steroidal anti-inflammatory drugs, aspirin and the risk of depression: The "Seguimiento Universidad de Navarra (SUN)" cohort.

BACKGROUND: The potential effect of Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) to prevent depression remains largely unknown, in spite of the implication of inflammation in depression. This study aimed to investigate whether the habitual intake of aspirin and other NSAIDs was prospectively associated with a reduction in the observed incidence of depression. METHODS: A dynamic cohort including 22,564 Spanish university graduates (mean age: 37 years) initially free of depression was followed during an average of 8.7 years. Exposure to NSAIDs was assessed with specific repeated questionnaires throughout follow-up, starting in the 2-year follow-up questionnaire. Incident cases of depression were defined as either a new validated medical diagnosis of depression or reporting the initiation of habitual use of antidepressants. RESULTS: We identified 772 incident cases of depression. Regular intake of aspirin and other NSAIDs was not associated with depression risk. Only in secondary sensitivity analyses using a definition of the outcome with higher specificity (a validated medical diagnosis of depression), an inverse association of aspirin with depression was found [HR (95%CI): 0.20 (0.04-0.87)]. However, these results were non-significant after adjustment for multiple testing. LIMITATIONS: A possible underestimation of incident depression and a limited ability to detect all possible residual confounding. CONCLUSIONS: Regular use of NSAIDs was not associated with the incidence of depression. Further longitudinal controlled studies are necessary to clarify a potential role of aspirin use in depression risk.