Validity and reliability of the Brazilian version of the Cognitive Reserve Assessment Scale in Health

Objective: As the older population increases, it is important to identify factors that may reduce the risks of dementia in the general population. One such factor is the concept of cognitive reserve (CR). The present study analyzed the psychometric properties of the Cognitive Reserve Assessment Scale in Health (CRASH) in the Brazilian population. This scale was originally developed to measure CR in individuals with severe mental illness. We also investigated the relationship between the CRASH and clinical or sociodemographic variables. Methods: This study was conducted with 398 individuals. We assessed sociodemographic variables and depression, anxiety, and stress symptoms (Depression, Anxiety and Stress Scale [DASS-21]) using a web-based survey. We constructed a confirmatory factor analysis (CFA) model in order to test the goodness of fit of the factor structure proposed in the original CRASH study. Results: The McDonald's hierarchical ω for CRASH using CFA parameters was 0.61, and the Cronbach's alpha coefficient indicated good internal consistency when considering all items (alpha = 0.7). Conclusions: Our results suggest that CRASH can be used to assess CR in the general population in Brazil.

Effects of Taurine in Mice and Zebrafish Behavioral Assays With Translational Relevance to Schizophrenia.

BACKGROUND: Altered redox state and developmental abnormalities in glutamatergic and GABAergic transmission during development are linked to the behavioral changes associated with schizophrenia. As an amino acid that exerts antioxidant and inhibitory actions in the brain, taurine is a potential candidate to modulate biological targets relevant to this disorder. Here, we investigated in mice and zebrafish assays whether taurine prevents the behavioral changes induced by acute administration of MK-801 (dizocilpine), a glutamate N-methyl-D-aspartate (NMDA) receptor antagonist. METHODS: C57BL/6 mice were i.p. administered with saline or taurine (50, 100, and 200 mg/kg) followed by MK-801 (0.15 mg/kg). Locomotor activity, social interaction, and prepulse inhibition of the acoustic startle reflex were then assessed in different sets of animals. Zebrafish were exposed to tank water or taurine (42, 150, and 400 mg/L) followed by MK-801 (5 µM); social preference and locomotor activity were evaluated in the same test. RESULTS: MK-801 induced hyperlocomotion and disrupted sensorimotor gating in mice; in zebrafish, it reduced sociability and increased locomotion. Taurine was mostly devoid of effects and did not counteract NMDA antagonism in mice or zebrafish. DISCUSSION: Contradicting previous clinical and preclinical data, taurine did not show antipsychotic-like effects in the present study. However, it still warrants consideration as a preventive intervention in animal models relevant to the prodromal phase of schizophrenia; further studies are thus necessary to evaluate whether and how taurine might benefit patients.

Psychological trauma as a transdiagnostic risk factor for mental disorder: an umbrella meta-analysis.

This umbrella review is the first to systematically examine psychological trauma as a transdiagnostic risk factor across psychiatric conditions. We searched Pubmed, Scopus, and PsycNET databases from inception until 01/05/2021 for systematic reviews/meta-analyses evaluating the association between psychological trauma and at least one diagnosed mental disorder. We re-calculated the odds ratio (OR), then classified the association as convincing, highly suggestive, suggestive, or weak, based on the number of cases and controls with and without psychological trauma, random-effects p value, the 95% confidence interval of the largest study, heterogeneity between studies, 95% prediction interval, small-study effect, and excess significance bias. Additional outcomes were the association between specific trauma types and specific mental disorders, and a sensitivity analysis for childhood trauma. Transdiagnosticity was assessed using TRANSD criteria. The review was pre-registered in Prospero CRD42020157308 and followed PRISMA/MOOSE guidelines. Fourteen reviews met inclusion criteria, comprising 16,277 cases and 77,586 controls. Psychological trauma met TRANSD criteria as a transdiagnostic factor across different diagnostic criteria and spectra. There was highly suggestive evidence of an association between psychological trauma at any time-point and any mental disorder (OR = 2.92) and between childhood trauma and any mental disorder (OR = 2.90). Regarding specific trauma types, convincing evidence linked physical abuse (OR = 2.36) and highly suggestive evidence linked sexual abuse (OR = 3.47) with a range of mental disorders, and convincing evidence linked emotional abuse to anxiety disorders (OR = 3.05); there were no data for emotional abuse with other disorders. These findings highlight the importance of preventing early traumatic events and providing trauma-informed care in early intervention and psychiatric services.

Mental health, functioning and quality of life between work in the office and work from home employees during first wave of COVID19 in Brazil.

BACKGROUND: COVID-19 was declared a global pandemic early in 2020, period that governments imposed strict measures of social distancing to slow its transmission. However, most essential services remained open, and the work in the office faced a higher risk of infection compared to work in home. We compare the occurrence and potential determinants of mental health outcomes, functioning and quality of life in a sample of Brazilian individuals who worked from home and those who worked in the office during the first wave of COVID-19. METHODS: Data were collected during the first wave of COVID-19, using an online survey to assess sociodemographic and clinical variables, functioning (FAST-D), quality of life (EUROhisQOL), depression (PROMIS depression), anxiety (PROMIS anxiety), and stress symptoms (IES-R scale) in a huge sample consisted of individuals who worked in office (n=1685) and worked from home (n=1338). RESULTS: Analysis revealed that depressive and post-traumatic stress symptoms were less prevalent in individuals who worked from home as well as they have higher functioning and quality of life than those worked in the office. Individuals who worked in the office were younger, more likely to be female, had lower household income level, low education levels and were more unmarried than the other group. CONCLUSION: Our findings support the notion of the negative impact of the COVID-19 pandemic on mental health in both work in the office and work from home; however, the group who worked from home seems to be more resilient with less psychiatric symptoms and better functioning.

Potential Candidates for Biomarkers in Bipolar Disorder: A Proteomic Approach through Systems Biology.

Bipolar disorder (BD) is one of the most disabling diseases characterized by severe humor fluctuation. It is accompanied by cognitive and functional impairment in addiction to high suicide rates. BD is often underdiagnosed and treated incorrectly because many of the reported symptoms are not exclusive to the disorder. Once the diagnosis is exclusively clinical, it is not possible to state precisely. From that, proteomic approaches were used to identify, in a large scale, all proteins involved in cellular or tissue processes. This review aggregate data from blood proteomes, by using protein association network, of subjects with BD and healthy controls to suggest dysfunctional molecular pathways involved in disease. Original articles containing proteomic analysis were searched in PubMed. Seven studies were selected and data were extracted for posterior analysis. A protein-protein interaction network was created by STRING database. A final set of proteins in this network were employed as input in ClueGO and, the main biological process was visualized using R package pathview. The analysis revealed proteins associated with many biological processes, including growth and endocrine regulation, iron transportation, protease inhibition, protection against pathogens and cholesterol transport. Moreover, pathway analysis indicated the association of uncovered proteins with two main metabolic pathways: complement system and coagulation cascade. Thus, a better understanding on the pathophysiology of psychiatric disorders and the identification of potential biomarker candidates are essential to improve diagnostic, prognostic and design pharmacological strategies.

Data-driven cognitive phenotypes in subjects with bipolar disorder and their clinical markers of severity.

BACKGROUND: Subjects with bipolar disorder (BD) show heterogeneous cognitive profile and that not necessarily the disease will lead to unfavorable clinical outcomes. We aimed to identify clinical markers of severity among cognitive clusters in individuals with BD through data-driven methods. METHODS: We recruited 167 outpatients with BD and 100 unaffected volunteers from Brazil and Spain that underwent a neuropsychological assessment. Cognitive functions assessed were inhibitory control, processing speed, cognitive flexibility, verbal fluency, working memory, short- and long-term verbal memory. We performed hierarchical cluster analysis and discriminant function analysis to determine and confirm cognitive clusters, respectively. Then, we used classification and regression tree (CART) algorithm to determine clinical and sociodemographic variables of the previously defined cognitive clusters. RESULTS: We identified three neuropsychological subgroups in individuals with BD: intact (35.3%), selectively impaired (34.7%), and severely impaired individuals (29.9%). The most important predictors of cognitive subgroups were years of education, the number of hospitalizations, and age, respectively. The model with CART algorithm showed sensitivity 45.8%, specificity 78.4%, balanced accuracy 62.1%, and the area under the ROC curve was 0.61. Of 10 attributes included in the model, only three variables were able to separate cognitive clusters in BD individuals: years of education, number of hospitalizations, and age. CONCLUSION: These results corroborate with recent findings of neuropsychological heterogeneity in BD, and suggest an overlapping between premorbid and morbid aspects that influence distinct cognitive courses of the disease.

Impact of the COVID-19 pandemic on mental health among local residents in South of Brazil: during pandemic times, youth sleep matters.

INTRODUCTION: Social isolation has been associated with poor sleep quality and mental health problems during the COVID-19 pandemic. However, most studies have investigated heterogeneous samples subjected to varying social distancing policies and did not focus on a single local profile subject to homogeneous prevention policies. OBJECTIVES: To evaluate the impact of the COVID-19 pandemic on mental health and sleep quality in a specific region in the South of Brazil where the populations have similar culture and local governments have adopted similar social distancing policies. METHODS: This study was conducted with 327 individuals aged 18-72 years, living in the Vale do Taquari area, Brazil. We assessed sociodemographic variables with a standardized protocol, symptoms of depression, anxiety, and stress with the Depression, Anxiety and Stress Scale-21 (DASS-21), sleep quality with the Pittsburgh Sleep Quality Index (PSQI), and post-traumatic stress symptoms with the Impact of Event Scale (IES-R), using a web-based online survey. RESULTS: Our results showed that sleep dysfunction moderated the effects of age on psychological symptoms, indicating that younger participants who had poorer sleep quality had worse mental health. Furthermore, participants with more perceived stress during the pandemic and more sleep dysfunction reported more symptoms of anxiety and post-traumatic stress. CONCLUSION: Psychological symptoms were not related to social isolation duration but were related to the subjective perception that the pandemic interfered with life and generated stressful situations. These results may help governments make important decisions about protection and isolation measures in future waves of COVID-19 infection.

Validity and Reliability of the Digital Functioning Assessment Short Test (D-FAST) in the Brazilian Sample.

Background: The COVID-19 pandemic has caused major disruptions in all aspects of daily functioning, from school and work to interactions with friends and family. The Functioning Assessment Short Test (FAST) is an interviewer-administered scale validated in the psychiatric sample with no previous study assessing its validity and reliability in a digital format. Thus, we aimed to analyse the psychometric properties of the digital version of the FAST and understand the implications of COVID-19 and restrictive measures on functioning. Methods: Data were collected using an online survey. The psychometric properties of the digital FAST were assessed by confirmatory factor analysis, Cronbach's alpha, and discriminant functional by cluster analysis in a community sample. Results: Out of the total sample, 2,543 (84.1%) were female, and the mean (SD) age was 34.28 (12.46) years. The digital FAST retained the six factors structure observed in the original version, with Cronbach's alpha above 0.9. In addition, we showed evidence of discriminant validity by differentiating three clusters of psychosocial functioning. Clinical and demographic differences between groups explained, in part, the heterogeneity of functioning, thus providing support for the construct validity of the instrument. Conclusion: The digital FAST is a simple and easy-to-understand instrument that provides a multidimensional assessment of functioning without the need for an interviewer. Furthermore, our findings may help to better understand the psychosocial implications of the pandemic and the importance of planning specific interventions to rehabilitee the affected group.

Impact of the COVID-19 pandemic on mental health among local residents in South of Brazil: during pandemic times, youth sleep matters

Abstract Introduction Social isolation has been associated with poor sleep quality and mental health problems during the COVID-19 pandemic. However, most studies have investigated heterogeneous samples subjected to varying social distancing policies and did not focus on a single local profile subject to homogeneous prevention policies. Objective To evaluate the impact of the COVID-19 pandemic on mental health and sleep quality in a specific region in the South of Brazil where the populations have similar culture and local governments have adopted similar social distancing policies. Methods This study was conducted with 327 individuals aged 18-72 years, living in the Vale do Taquari area, Brazil. We assessed sociodemographic variables with a standardized protocol, symptoms of depression, anxiety, and stress with the Depression, Anxiety and Stress Scale-21 (DASS-21), sleep quality with the Pittsburgh Sleep Quality Index (PSQI), and post-traumatic stress symptoms with the Impact of Event Scale (IES-R), using a web-based online survey. Results Our results showed that sleep dysfunction moderated the effects of age on psychological symptoms, indicating that younger participants who had poorer sleep quality had worse mental health. Furthermore, participants with more perceived stress during the pandemic and more sleep dysfunction reported more symptoms of anxiety and post-traumatic stress. Conclusion Psychological symptoms were not related to social isolation duration but were related to the subjective perception that the pandemic interfered with life and generated stressful situations. These results may help governments make important decisions about protection and isolation measures in future waves of COVID-19 infection.

Cognitive clusters in first-episode psychosis.

Impairments in a broad range of cognitive domains have been consistently reported in some individuals with first-episode psychosis (FEP). Cognitive deficits can be observed during the prodromal stage. However, the course of cognitive deficits is still unclear. The aim of this study was to identify cognitive subgroups over time and to compare their sociodemographic, clinical and functional profiles. A total of 114 patients with Schizophrenia Spectrum Disorders were included in the present study. We assessed subjects through psychiatric scales and eight neuropsychological tests at baseline and at two-year follow-up visit. We performed the Partition Around Medoids algorithm with all cognitive variables. Furthermore, we performed a logistic regression to identify the predictors related to the different cognitive clusters at follow-up. Two distinct subgroups were found: the first cluster characterized by cognitive impairment and a second cluster had relatively intact cognition in comparison with norms. Up to 54.7% of patients with cognitive deficits at baseline tended to improve during the first two years of treatment. Patients with intact cognition at follow-up had a higher socioeconomic status, later age of onset, lower negative symptoms and a higher cognitive reserve (CR) at baseline. CR and age of onset were the baseline variables that predicted cognitive impairment. This research allows us to obtain a better understanding of the heterogeneous profile of psychotic disorders. Identifying the characteristics of patients who will present a cognitive impairment could improve early detection and intervention. These results suggest that enhancing CR could contribute to improving the course of the illness.

Anti-stress effects of the glucagon-like peptide-1 receptor agonist liraglutide in zebrafish.

Stress-related disorders are extremely harmful and cause significant impacts on the individual and society. Despite the limited evidence regarding glucagon-like peptide-1 receptor (GLP-1R) and mental disorders, a few clinical and preclinical studies suggest that modulating this system could improve symptoms of stress-related disorders. This study aimed to investigate the effects of liraglutide, a GLP-1R agonist, on neurobehavioral phenotypes and brain oxidative status in adult zebrafish. Acute liraglutide promoted anxiolytic-like effects in the light/dark test, while chronic treatment blocked the impact of unpredictable chronic stress on behavioral and physiological parameters. Taken together, our study demonstrates that liraglutide is active on the zebrafish brain and may counteract some of the effects induced by stress. More studies are warranted to further elucidate the potential of GLP-1R agonists for the management of brain disorders.

COVID-19 and mental health in Brazil: Psychiatric symptoms in the general population.

Public health interventions at general population level are imperative in order to decrease the spread of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), but they may contribute to widespread emotional distress and increased risk for psychiatric illnesses. We report on the results of an investigation into the occurrence and determinants of psychiatric symptoms among the Brazilian general population (N = 1996). We assessed sociodemographic variables and general mental health (DSM-5 Self-Rated Level 1 Cross-Cutting Symptom Measure), depression (PROMIS depression v.8a), anxiety (PROMIS anxiety v.8a), and post-traumatic stress symptoms (Impact of Event Scale-IES-R scale) using an online web-based survey. Anxiety (81.9%), depression (68%), anger (64.5%), somatic symptoms (62.6%) and sleep problems (55.3%) were the most common psychiatric symptoms. Younger age, female gender, low income, lower level of education, longer period of social distancing, and self-reported history of previous psychiatric illness were strongly associated with higher severity of symptoms. Our results support the negative impact of the COVID-19 pandemic on the mental health of the Brazilian population. The high prevalence of psychiatric symptoms observed in our sample indicates that the mental health impact of the COVID-19 pandemic should be considered a public health problem in Brazil. The health systems and individual clinicians must be prepared to offer and implement specific interventions in order to identify and treat psychiatric issues.

O impacto da primeira onda da pandemia de Covid-19 na saúde mental de estudantes brasileiros / The impact of the first wave of the Covid-19 pandemic on the mental health of Brazilian students

Com a alta disseminação do novo coronavírus, foi necessário adotar intervenções de saúde pública com foco no distanciamento social para diminuir a transmissão do patógeno causador, o SARS-Cov-2. Contudo, essas medidas podem contribuir para o aumento do sofrimento emocional, gerando níveis mais elevados de ansiedade, depressão e estresse. Desse modo, o objetivo deste estudo foi investigar os efeitos da pandemia de Covid-19 na saúde mental de estudantes brasileiros através de uma pesquisa levantamento de dados on-line. A pesquisa foi realizada durante o período da primeira onda da pandemia no Brasil. Foram avaliadas variáveis sociodemográficas, de saúde mental, incluindo sintomas de depressão e ansiedade, e qualidade de vida em uma amostra final de 810 estudantes. Os sintomas psiquiátricos mais prevalentes foram ansiedade (89,5%), depressão (77,9%) e raiva (72,3%). Tempo de distanciamento social, idade e diagnóstico prévio de doenças psiquiátricas foram significativamente associados à maior gravidade dos sintomas de ansiedade e depressão. O alto grau de sofrimento emocional apresentado por essa amostra indica a necessidade de adotar estratégias que visem promover a saúde mental de estudantes, e proporcionar acompanhamento psicológico de alunos durante e após esse período crítico de isolamento social.(AU)

With the high spread of the new coronavirus, it was necessary to adopt public health interventions focused on social distancing to reduce the transmission of the causative pathogen, SARS-Cov-2. However, these measures can contribute to increased emotional distress, generating higher levels of anxiety, depression and stress. Thus, the aim of this study was to investigate the effects of the Covid-19 pandemic on the mental health of Brazilian students through an online data collection survey. The survey was carried out during the period of the first wave of the pandemic in Brazil. Sociodemographic, mental health (e.g., symptoms of depression and anxiety), and quality of life variables were evaluated in a final sample of 810 students. The most prevalent psychiatric symptoms were anxiety (89.5%), depression (77.9%) and anger (72.3%). Time of social distancing, age and previous diagnosis of psychiatric illness were significantly associated with greater severity of anxiety and depression symptoms. The high degree of emotional distress presented by this sample indicates the need to adopt strategies aimed at promoting the mental health of students and providing psychological support for students during and after this critical period of social isolation.(AU)

Con la alta propagación del nuevo coronavirus, fue necesario adoptar intervenciones de salud pública enfocadas en el distanciamiento social para reducir la transmisión del patógeno causante, SARS-Cov-2. Sin embargo, estas medidas pueden contribuir a aumentar la angustia emocional, generando mayores niveles de ansiedad, depresión y estrés. Por lo tanto, el objetivo de este estudio fue investigar los efectos de la pandemia Covid-19 en la salud mental de los estudiantes brasileños a través de una encuesta de recolección de datos en línea. La encuesta se llevó a cabo durante el período de la primera ola de la pandemia en Brasil. Se evaluaron variables sociodemográficas, de salud mental, incluyendo síntomas de depresión y ansiedad, y calidad de vida en una muestra final de 810 estudiantes. Los síntomas psiquiátricos más prevalentes fueron ansiedad (89,5%), depresión (77,9%) e ira (72,3%). El tiempo de distanciamiento social, la edad y el diagnóstico previo de enfermedad psiquiátrica se asociaron significativamente con una mayor gravedad de los síntomas de ansiedad y depresión. El alto grado de angustia emocional que presenta esta muestra indica la necesidad de adoptar estrategias dirigidas a promover la salud mental de los estudiantes y brindar apoyo psicológico a los estudiantes durante y después de este período crítico de aislamiento social.(AU)

Targeting Inflammatory-Mitochondrial Response in Major Depression: Current Evidence and Further Challenges.

The prevalence of psychiatric disorders has increased in recent years. Among existing mental disorders, major depressive disorder (MDD) has emerged as one of the leading causes of disability worldwide, affecting individuals throughout their lives. Currently, MDD affects 15% of adults in the Americas. Over the past 50 years, pharmacotherapy, psychotherapy, and brain stimulation have been used to treat MDD. The most common approach is still pharmacotherapy; however, studies show that about 40% of patients are refractory to existing treatments. Although the monoamine hypothesis has been widely accepted as a molecular mechanism to explain the etiology of depression, its relationship with other biochemical phenomena remains only partially understood. This is the case of the link between MDD and inflammation, mitochondrial dysfunction, and oxidative stress. Studies have found that depressive patients usually exhibit altered inflammatory markers, mitochondrial membrane depolarization, oxidized mitochondrial DNA, and thus high levels of both central and peripheral reactive oxygen species (ROS). The effect of antidepressants on these events remains unclear. Nevertheless, the effects of ROS on the brain are well known, including lipid peroxidation of neuronal membranes, accumulation of peroxidation products in neurons, protein and DNA damage, reduced antioxidant defenses, apoptosis induction, and neuroinflammation. Antioxidants such as ascorbic acid, tocopherols, and coenzyme Q have shown promise in some depressive patients, but without consensus on their efficacy. Hence, this paper provides a review of MDD and its association with inflammation, mitochondrial dysfunction, and oxidative stress and is aimed at thoroughly discussing the putative links between these events, which may contribute to the design and development of new therapeutic approaches for patients.

Perceived childhood adversities: Impact of childhood trauma to estimated intellectual functioning of individuals with bipolar disorder.

Maltreatments in childhood may have implications for neurodevelopment that could remain throughout life. Childhood trauma seems to be associated with the onset of bipolar disorder (BD), and its occurrence might accentuate the overall disease impairments related to cognitive deficits in BD. We aimed to evaluate the effects of a history of childhood trauma to estimated intellectual functioning (IQ) of individuals with BD. We included 72 subjects with BD during euthymia. Participants underwent a clinical interview and were assessed through the Childhood Trauma Questionnaire (CTQ) and Wechsler Abbreviated Scale of Intelligence (WASI). Most prevalent trauma subtypes were emotional abuse and neglect (54.1%). A linear regression model that included perceived childhood trauma, family history of severe mental disorders, age at diagnosis and psychotic symptoms during the first episode as main factors showed that only childhood trauma had a significant effect in predicting estimated IQ. Therefore, the history of childhood trauma in individuals with BD may play a role in intellectual development, suggesting that adversities during development result in decreased general cognitive abilities. These results reinforce the need to promote early interventions to protect childhood and to promote the well-being of children, contributing to the growth of healthy adults.

Depression and Mania Induce Pro-inflammatory Activation of Macrophages Following Application of Serum from Individuals with Bipolar Disorder.

OBJECTIVE: Evidence has suggested that immune imbalance is involved with bipolar disorder (BD); however, its precise mechanism is poorly understood. This study investigated whether biochemical changes in the serum from BD patients could modulate the phenotype of cultured macrophages. METHODS: Eighteen subjects with BD and five healthy individuals were included in this study. The human monocyte cell line U-937 was activated with phorbol 12-myristate 13-acetate (PMA) and polarization was induced with RPMI-1640 media supplemented with 10% serum from each patient for 24 hours. Gene expression of selected M1 and M2 markers was assessed by quantitative PCR. RESULTS: Macrophages exposed to serum of manic and depressive BD patients displayed an increase of interleukin-1ß (6.40±3.47 and 9.04±5.84 vs. 0.23±0.11; p＜0.05) and tumor necrosis factor-α (2.23±0.91 and 2.03±0.45 vs. 0.62±0.24; p=0.002 and p=0.004, respectively) compared to euthymic group (there was no difference between euthymic and controls). In parallel, U-937 macrophages treated with serum of patients in acute episode displayed a down-regulation of CXCL9 (0.29±0.20 vs. 1.86±1.61; p=0.006) and CXCL10 expression (0.36±0.15 and 0.86±0.24 vs. 1.83±0.88; p＜0.000 and p=0.04) compared to the euthymia group. CONCLUSION: Our results are consistent with previous studies showing that changes in peripheral blood markers could modulate M1/M2 polarization in BD. The evidence of macrophages as source of inflammatory cytokines might be helpful to unravel how the mononuclear phagocyte system is involved in the etiology of BD.

Telomere Length, Oxidative Stress, Inflammation and BDNF Levels in Siblings of Patients with Bipolar Disorder: Implications for Accelerated Cellular Aging.

Background: Growing evidence supports the existence of neurobiological trait abnormalities in individuals at genetic risk for bipolar disorder. The aim of this study was to examine potential differences in brain-derived neurotrophic factor, cytokines, oxidative stress, and telomere length markers between patients with bipolar disorder, their siblings, and healthy controls. Methods: Thirty-six patients with bipolar disorder type I, 39 siblings, and 44 healthy controls were assessed. Serum levels of brain-derived neurotrophic factor, interleukin-6, interleukin-10, tumor necrosis factor-α, C-C motif chemokine 11, C-C motif chemokine 24, and 3-nitrotyrosine were measured, as were the activities of glutathione peroxidase, glutathione reductase, and glutathione S-transferase. Telomere length (T/S ratio) was measured using quantitative polymerase chain reaction. Results: Telomere length was different between the 3 groups (P = .041) with both patients and siblings showing a shorter T/S ratio compared with healthy controls. Patients showed increased levels of interleukin-6 (P = .005) and interleukin-10 (P = .002) compared with controls as well as increased levels of interleukin-6 (p = 0.014) and CCL24 (P = .016) compared with their siblings. C-C motif chemokine 11 levels were increased in siblings compared with controls (P = .015), and a similar tendency was found in patients compared with controls (P = .045). Glutathione peroxidase activity was decreased in patients compared with controls (P = .006) and siblings (P = .025). No differences were found for the other markers. Conclusions: The present results suggest that unaffected siblings may present accelerated aging features. These neurobiological findings may be considered as endophenotypic traits. Further prospective studies are warranted.

Hippocampal neurochemical markers in bipolar disorder patients following the first-manic episode: A prospective 12-month proton magnetic resonance spectroscopy study.

OBJECTIVE: Previous studies reported decreased N-acetyl aspartate and increased Glx (the sum of glutamate plus glutamine) in bipolar disorder. Since these studies included patients at different stages of illness, it is unknown whether these changes have a causal role or a consequence of multiple episodes and treatments. The studies in early-stage bipolar disorder patients have the potential to provide answers to these issues. Therefore, we evaluated N-acetyl aspartate and Glx levels in hippocampi of first-episode bipolar disorder patients and health subjects at baseline and at 12 months, and examined the impact of episode recurrence on these measures. METHOD: We used single-voxel proton magnetic resonance spectroscopy to compare the hippocampal neurometabolites ( N-acetyl aspartate and Glx) levels between 41 patients with bipolar disorder following recovery from their first-manic episode and 27 matched healthy subjects at recruitment and 12 months later. We also compared N-acetyl aspartate and Glx levels between patients who had a recurrence of a mood episode and those who did not. RESULTS: There was no main effect of either group (diagnosis) or time for hippocampal N-acetyl aspartate and Glx levels in bipolar disorder patients and healthy subjects. We also did not find any group-by-time interaction for the levels of these metabolites. There were also no differences in N-acetyl aspartate and Glx between patients who experienced a recurrence of a mood episode and those who did not over 12-month follow-up. CONCLUSION: Our data suggest that N-acetyl aspartate and Glx levels are not altered in early stage bipolar disorder. Further, these data suggest that episode recurrence in early stages does not have a significant impact on the levels of these metabolites. These may suggest that there may be an early window for intervention to potentially arrest neuroprogression of the disease.

The role of macrophage polarization on bipolar disorder: Identifying new therapeutic targets.

OBJECTIVE: Bipolar disorder is a chronic, severe and disabling disease; however, its pathophysiology remains poorly understood. Recent evidence has suggested that inflammation and immune dysregulation play a significant role in the pathophysiology of bipolar disorder. This review is aimed to highlight the importance of systemic inflammation in modulating the inflammatory response of microglia and hence its potential involvement with bipolar disorder. We also discuss novel therapeutic strategies that emerge from this new research. METHOD: This article presents a theoretical synthesis of the effects of systemic inflammation on the immune response of the central nervous system in bipolar disorder. The complex relationship between stress, pro-inflammatory cytokines and microglial dysfunction is summarized, emphasizing the role of the kynurenine pathway in this process and, consequently, their effects on neuronal plasticity. RESULTS: Bipolar patients demonstrate increased serum levels of pro-inflammatory cytokines (interleukin-1ß, interleukin-6 and tumor necrosis factor-α) and lower hypothalamic-pituitary-adrenal axis sensitivity. This imbalance in the immune system promotes a change in blood-brain barrier permeability, leading to an inflammatory signal spread in the central nervous system from the periphery, through macrophages activation (M1 polarization). Chronic microglial activation can result in neuronal apoptosis, neurogenesis inhibition, hippocampal volume reduction, lower neurotransmitters synthesis and cytotoxicity, by increasing glutamate production and kynurenine metabolism. CONCLUSIONS: This review provides an overview of the mechanisms involved in the immune system imbalance and its potential involvement in the pathophysiology of bipolar disorder. Consequently, new strategies that normalize the immune-inflammatory pathways may provide a valuable therapeutic target for the treatment of these disorders.