Chemokines in bipolar disorder: trait or state?

Recent evidence has suggested that inflammatory and immune mechanisms may play a role in the pathophysiology of bipolar disorder (BD). Only a few studies have assessed the profile of chemokines, a family of chemotactic cytokines related to the recruitment of leukocytes, in BD. The objective of our study was to evaluate the plasma levels of chemokines in BD patients in different mood states in comparison with healthy controls. Seventy BD type I patients (35 in euthymia and 35 in mania), and 50 healthy controls matched by age, gender, and education level were enrolled in this study. All subjects were assessed by the Mini-International Neuropsychiatry Interview and the patients by the Young Mania Rating Scale and the Hamilton Depression Rating Scale. The plasma levels of CCL2, CCL3, CCL11, CCL24, CXCL8, and CXCL10 were measured by enzyme-linked immunosorbent assay. BD patients presented higher plasma levels of CCL11 (1.69-fold increase; p < 0.001), CCL24 (1.40-fold increase; p = 0.02), CXCL10 (1.45-fold increase; p < 0.001) and decreased plasma levels of CXCL8 (8.68-fold decrease p < 0.001). Logistic regression stressed the main effect of increased plasma levels of CXCL10 (OR = 1.009, 95 % CI = 1.000-1.018, p = 0.042) and CCL11 (OR = 1.002, 95 % CI = 1.001-1.003, p = 0.003) and decreased plasma levels of CXCL8 (OR = 0.995, 95 % CI = 0.990-0.999, p = 0.013) to BD. This study reinforces the view that BD is associated with an immune dysfunction.

Increased plasma levels of soluble TNF receptor I in patients with bipolar disorder.

Bipolar disorder (BD) has been associated with a proinflammatory state in which TNF-α seems to play a relevant role. The aim of the present study was to evaluate the plasma levels of TNF-α and its soluble receptors (sTNFR1 and sTNFR2) in BD patients in mania and euthymia in comparison with control subjects. We evaluated 53 BD patients (34 in mania and 19 in euthymia) and 38 healthy subjects. All subjects were assessed by the Mini-International Neuropsychiatry Interview (MINI-Plus). Patients were also evaluated by the Young Mania Rating Scale (YMRS) and by Hamilton Depression Rating Scale (HDRS). Plasma TNF-α and its soluble receptors were measured by ELISA. The plasma TNF-α and sTNFR2 levels did not differ between groups, but higher sTNFR1 levels were found in BD patients. Of note, BD patients in mania had higher sTNFR1 levels than BD patients in euthymia and controls. The sTNFR1 and sTNFR2 levels correlated with BD duration, and sTNFR2 levels correlated with age of patients. Our data indicate a proinflammatory status in BD patients during mania and further suggest that inflammatory mechanisms may be involved with the physiopathology of BD.

Childhood trauma is associated with age at onset of symptoms, functioning, and cognition in patients with schizophrenia

Abstract Introduction Childhood trauma (CT) is known to be a vulnerability factor for schizophrenia, but the specific impacts of different trauma subtypes on the prognosis of these patients remains unclear. Objective To assess the relationships between the occurrence of overall CT and its subtypes with factors with known prognostic impact on schizophrenia, such as age at onset of symptoms, global functioning, and cognitive impairment in a sample of Brazilian patients. Methods One hundred and five stable patients diagnosed with schizophrenia according to DSM-5 criteria were evaluated using the Independent Living Skills Survey (ILSS; self-report global functioning), Schizophrenia Cognition Rating Scale (SCoRS; subjective cognitive impairment), and Childhood Trauma Questionnaire scales (CTQ; perceived overall CT, emotional neglect, physical neglect, physical abuse, and emotional and sexual abuse). Statistical analysis was performed with multivariate linear regression. Results After controlling for educational level and age, subjective cognitive impairment was directly correlated with overall perceived CT occurrence, emotional abuse, and sexual abuse. Self-report global functioning was inversely correlated with perceived overall CT occurrence, emotional abuse, and sexual abuse. Emotional abuse and physical abuse were also inversely correlated with age at onset of symptoms. Conclusions CT can be related to more severe prognoses in schizophrenia, impacting on early onset of symptoms, lower global functioning, and greater cognitive impairment. Subtypes of trauma can be associated with different prognostic risks.

Klotho dysfunction: A pathway linking the aging process to bipolar disorder?

AIM: Although accelerated aging profile has been described in bipolar disorder (BD), the biology linking BD and aging is still largely unknown. Reduced levels and/or activity of a protein named Klotho is associated with decreased life span, premature aging and occurrence of age-related diseases. Therefore, this study was designed to evaluate plasma levels of Klotho in BD patients and controls. METHODS: Forty patients with type 1 BD and 30 controls were enrolled in this study. After clinical evaluation, peripheral blood samples were drawn and plasma levels of Klotho were measured using enzyme-linked immunosorbent assay. RESULTS: Patients with BD and controls presented similar age and sex distribution. The mean ± SD length of illness was 24.00 ± 12.75 years. BD patients presented increased frequency of clinical comorbidities in comparison with controls, mainly arterial hypertension, diabetes mellitus, and hypothyroidism. Both patients with BD in remission and in mania exhibited increased plasma levels of Klotho in comparison with controls. There was no significant difference between patients in mania and patients in remission regarding the levels of Klotho. CONCLUSION: Klotho-related pathway is altered in BD. Contrary to our original hypothesis, our sample of patients with BD presented increased plasma levels of Klotho in comparison with controls. Elevated levels of Klotho in long-term BD patients may be associated with the disorder progression. Further studies are needed to better understand the role of Klotho in BD and other mood disorders.

Increased BDNF levels in long-term bipolar disorder patients.

INTRODUCTION: Bipolar disorder (BD) is a prevalent, chronic and progressive illness. There is a growing body of evidence indicating that brain-derived neurotrophic factor (BDNF) plays an important role in the pathophysiology of BD. OBJECTIVE: The aim of this study was to evaluate BDNF plasma levels in BD patients with long term illness in comparison with controls. METHODS: 87 BD type I patients and 58 controls matched by age, gender and education level were enrolled in this study. All subjects were assessed by the Mini-International Neuropsychiatric Interview and the patients by the Young Mania Rating Scale and the Hamilton Depression Rating Scale. The plasma levels of BDNF were measured by ELISA. RESULTS: On average, patients had suffered from BD for 23.4 years. In comparison with controls, BD patients with mania presented a 1.90-fold increase in BDNF plasma levels (p = .001), while BD patients in remission presented a 1.64-fold increase in BDNF plasma levels (p = .03). BDNF plasma levels were not influenced by age, length of illness or current medications. CONCLUSIONS: The present study suggests that long-term BD patients exhibit increased circulating levels of BDNF.

Altered intracellular signaling cascades in peripheral blood mononuclear cells from BD patients.

Bipolar disorder (BD) is a severe psychiatric disorder of complex physiopathology that has been associated with a pro-inflammatory state. The aim of the present study was to investigate intracellular pathways associated with inflammatory signaling, assessing the phosphorylation levels of transcription factor nuclear factor kappa B (NF-κB) and mitogen-activated protein kinase (MAPKs) in peripheral blood mononuclear cells of euthymic BD patients and healthy controls. Fifteen BD euthymic type I patients, and 12 healthy controls matched by age and gender were enrolled in this study. All subjects were assessed by the Mini-International Neuropsychiatry Interview and the patients also by the Young Mania Rating Scale and the Hamilton Depression Rating Scale. Phosphorylation levels of p65 NF-κB subunit, and MAPK ERK1/2, and p38 were assessed by Western blot and flow cytometry. Plasma cytokines (IL-2, IL-4, IL6, IL-10, IFN-γ, TNF-α, and IL-17A) were measured using cytometric bead arrays. Western blot and flow cytometry analyses showed increased phosphorylation levels of p65 NF-κB subunit, and MAPKs ERK1/2, and p38 in BD patients in euthymia in comparison with controls. BD patients presented increased pro-inflammatory cytokines levels in comparison with controls, and TNF-α correlated with the levels of phosphorylated p65 NF-κB. The present study found increased activation of MAPK and NF-κB pathways in BD patients, which is in line with a pro-inflammatory status.

Executive dysfunction in euthymic bipolar disorder patients and its association with plasma biomarkers.

BACKGROUND: Despite the old Kraepelinean concept that bipolar disorder (BD) does not evolve with cognitive decline, the presence of cognitive impairment, especially executive dysfunction has been recognized in BD patients. Brain-derived neurotrophic factor (BDNF) and pro-inflammatory molecules are important contributors to the pathophysiology of BD, and imbalance in peripheral levels of these molecules may be implicated in the cognitive decline observed in BD patients. We aimed to investigate the executive performance of BD type I euthymic patients and its relation with the plasma levels of BDNF, TNF-α and its related soluble receptors (sTNFR1 and sTNFR2). METHODS: We evaluated executive functioning through the Frontal Assessment Battery (FAB). Plasma levels of BDNF, TNF-α, sTNFR1 and sTNFR2 were measured using enzyme-linked immunosorbent assay (ELISA) in 25 euthymic type I BD patients and 25 age and gender matched healthy controls. RESULTS: BD patients had an impairment in executive functioning (p<0.006), particularly sensitivity of interference (p=0.02), inhibitory control (p=0.02), and increased BDNF plasma levels (p=0.001) in comparison with controls. Plasma levels of TNF-α were correlated with inhibitory control in BD patients (ρ=0.50, p=0.02) while motor programming was negatively correlated with sTNFR2 plasma levels (ρ=-0.47, p=0.02) in controls. Executive function correlated with age and MMSE, but not with BDNF, neither was influenced by psychiatric and clinical comorbidities nor medications in use. CONCLUSION: BDNF is altered in BD but do not correlate with executive functioning.

Increased levels of adipokines in bipolar disorder.

Bipolar disorder (BD) is associated with considerable higher chronic medical comorbidities, overweight and obesity. Adipokines are adipocyte-derived secretory factors which have functions in immune response and seem to be associated with both BD and overweight. The aim of this study was to evaluate the plasma levels of adipokines (adiponectin, resistin and leptin) and TNF-α and its receptors (sTNFR1 and sTNFR2) in BD overweight patients in comparison with overweight controls. Thirty euthymic BD type-I patients and thirty controls matched by age, gender and body-mass index (BMI) were assessed by Mini-International Neuropsychiatric Interview, Young Mania and Hamilton Depression rating scales (YMRS and HDRS, respectively). Plasma levels of adiponectin, resistin, leptin, TNF-α and its soluble receptors were measured by ELISA. BD patients presented increased plasma levels of adiponectin (p < 0.001), leptin (p < 0.001) and sTNFR1 (p = 0.01). Plasma levels of adipokines were not correlated neither with clinical parameters nor TNF-α, sTNFR1 and sTNFR2 plasma levels. This study provides further support to the hypothesis of the immune/inflammatory imbalance in BD.

Impaired nerve growth factor homeostasis in patients with bipolar disorder.

OBJECTIVE: Neuro-trophins are critically involved in neuro-plasticity, the impairment of which is a major role-player in bipolar disorder (BD), and their altered levels have been recently advocated in the patho-physiology of this affective malady. The aim of this study, therefore, was to evaluate the plasma levels of nerve growth factor (NGF) in BD patients in comparison with control subjects. METHODS: Forty-nine BD type-I individuals (30 in mania and 19 in euthymia) and 36 healthy controls were assessed by Mini-plus, Young mania and Hamilton depression rating scales. NGF levels were detected by ELISA. RESULTS: Plasma NGF concentrations were decreased in BD patients when compared to that seen with controls. BD individuals in mania had lower NGF levels than euthymic patients or controls. NGF levels were negatively correlated with the severity of mania. CONCLUSIONS: This is the first study to evaluate NGF levels in BD patients, providing further support to the hypothesis of impaired neuro-plasticity in BD. These data also suggest that NGF measurement could be used for the biological marker for manic state.

Circulating levels of GDNF in bipolar disorder.

Neurotrophic factors regulate the survival and growth of neurons, and influence synaptic efficiency and plasticity. Several studies suggest the existence of a relationship between changes in neurotrophic levels and bipolar disorder (BD). The glial cell-line derived neurotrophic factor (GDNF) influences monoaminergic neurons and glial cells, but its role in BD patients is controversial. In order to elucidate it we evaluated plasma levels of GDNF in a sample of 70 BD patients (35 in mania and 35 in euthymia) and compared with 50 healthy controls matched for age, gender and educational levels. GDNF plasma levels were measured by enzyme-linked immunosorbent assay (ELISA). Patients were assessed by a Mini-International Neuropsychiatric Interview (MINI-plus), Young Mania and Hamilton Depression Rating Scales. Plasma GDNF levels were significantly increased in BD patients in euthymia compared with BD patients in mania and healthy controls (p<0.05). GDNF plasma levels were correlated with age (ρ=0.30, p<0.05) and negatively correlated with manic symptoms in BD patients (ρ=-0.54, p<0.05). Our results provide evidence that peripheral levels of GDNF are related with different mood states in BD, reinforcing the involvement of neurotrophic factors in its physiopathology.

Increased plasma levels of brain-derived neurotrophic factor in patients with long-term bipolar disorder.

Recent data indicate that neurotrophins may play a role in the physiopathology of bipolar disorder (BD) and may be useful as biomarkers of the disease. The aim of this study was to evaluate the plasma concentrations of brain-derived neurotrophic factor (BDNF) in BD patients, and to correlate their levels with clinical parameters. BDNF was measured in plasma from 53 BD type I subjects (34 during mania and 19 during euthymia) and 38 healthy controls by enzyme-linked immuno-sorbent assay (ELISA). Patients were assessed by a structured clinical interview (Mini-plus), Young mania and Hamilton depression rating scales. Plasma BDNF levels were significantly increased in patients with mania (P

Comorbidades clínicas e psiquiátricas em pacientes com transtorno bipolar do tipo I / Psychiatric and medical comorbidities in type 1 bipolar disorder patients

Contexto: O transtorno bipolar tipo I está comumente associado a comorbidades clínicas e psiquiátricas, mas ainda há poucos dados disponíveis sobre pacientes brasileiros. Objetivos: O objetivo do presente estudo foi avaliar a prevalência de comorbidades clínicas e psiquiátricas em uma amostra brasileira de pacientes bipolares tipo I. O objetivo secundário foi investigar as associações de características clínico-demográficas e comorbidades com tentativas de suicídio. Métodos: Foram incluídos neste estudo 94 pacientes bipolares tipo I. O diagnóstico psiquiátrico foi determinado utilizando-se a avaliação Mini International Neuropsychiatric Interview (MINI-Plus). O diagnóstico de comorbidades clínicas foi baseado na história clínica e no acompanhamento de clínicos gerais. Resultados: As comorbidades mais prevalentes nos pacientes bipolares foram: transtorno de ansiedade generalizada (19,20 por cento), dependência de substâncias (43,60 por cento), hipertensão arterial (29,80 por cento), diabetes mellitus (17,00 por cento), dislipidemia (22,30 por cento) e hipotireoidismo (19,10 por cento). Não foram encontradas diferenças estatísticas em relação às características demográficas ou à prevalência de comorbidades nos grupos com e sem tentativa de suicídio. Conclusão: Pacientes bipolares atendidos em serviço psiquiátrico apresentam elevada prevalência de comorbidades psiquiátricas e clínicas. Nessa população, tentativas de suicídio não se associam com a presença de comorbidades ou características demográficas.

Background: Bipolar disorder type I is frequently associated with psychiatric and medical comorbidities, but data regarding Brazilian patients are lacking. Objectives: The aim of the present study was to evaluate the prevalence of psychiatric and medical comorbidities in a Brazilian sample of bipolar disorder patients type I. A secondary aim was to investigate the association of demographic characteristics and comorbidities with suicide attempts. Methods: Ninety four bipolar disorder type I patients were included in this study. Psychiatric diagnoses were performed following the Mini International Neuropsychiatric Interview (MINI-Plus) evaluation. The diagnosis of medical comorbidities was based on clinical history and general practice consultation. Results: The commonest comorbidities in bipolar disorder patients were generalized anxiety disorder (19.20 percent), substance dependence (43.60 percent), arterial hypertension (29.80 percent), diabetes mellitus (17.00 percent), dyslipidemia (22.30 percent) and hypothyroidism (19.10 percent). There were no differences in demographic characteristics or the prevalence of comorbidities when comparing patients with and without previous suicide attempt. Conclusion: Bipolar disorder patients from a psychiatric unit present higher prevalence of psychiatric and clinical comorbidities. Previous suicide attempts were not associated with comorbidities or demographic characteristics.

Imunologia do transtorno bipolar: [revisão] / Immunology of bipolar disorder

OBJETIVO: Pesquisas recentes têm implicado fatores imunes na patogênese de diversos transtornos neuropsiquiátricos. O objetivo do presente trabalho é revisar os trabalhos que investigaram a associação entre transtorno bipolar e alterações em parâmetros imunes. MÉTODOS: Artigos que incluíam as palavras-chave: "bipolar disorder", "mania", "immunology", "cytokines", "chemokines", "interleukins", "interferon" e "tumor necrosis factor" foram selecionados em uma revisão sistemática da literatura. As bases de dados avaliadas foram MedLine e Scopus, entre os anos de 1980 e 2008. RESULTADOS: Foram identificados 28 trabalhos que estudaram alterações imunes em pacientes com transtorno bipolar. Seis artigos investigaram genes relacionados à resposta imune; cinco, autoanticorpos; quatro, populações leucocitárias; 13, citocinas e/ou moléculas relacionadas à resposta imune e seis, leucócitos de pacientes in vitro. CONCLUSÕES: Embora haja evidências na literatura correlacionando o transtorno bipolar a alterações imunes, os dados não são conclusivos. O transtorno bipolar parece estar associado a níveis mais elevados de autoanticorpos circulantes, assim como à tendência à ativação imune com produção de citocinas pró-inflamatórias e redução de parâmetros anti-inflamatórios.

OBJECTIVE: Emerging research has implicated immune factors in the pathogenesis of a variety of neuropsychiatric disorders. The objective of the present paper is to review the studies that investigated the association between bipolar disorder and immune parameters. METHODS: Papers that included the keywords "bipolar to disorder", "mania", "immunology", "cytokines", "chemokines", "interleukins", "interferon" and "tumor necrosis factor" were selected in a systematic review of the literature. The evaluated databases were MedLine and Scopus in the period between 1980 and 2008. RESULTS: Twenty eight works were found. Six studies investigated immune response-related genes; five, auto-antibodies; four, leukocyte population; 13, cytokines and/or immune-related molecules; six, leukocytes in vitro. CONCLUSIONS: Although there is evidence in the literature correlating affective disorders with immune parameters, the results are still inconclusive. Bipolar disorder seems to be associated with increased levels of auto-antibodies as well as with a trend for increased immune activation with production of pro-inflammatory cytokines and reduction of the anti-inflammatory parameters.

Trombocitopenia intensa como fator decisivo sobre a evolução de paciente com lupus erimatoso sistêmico / Systemic lupus erythematosus evolution associated and aggravated by severe thrombocytopenia

A paciente MLC, de 46 anos, portadora de lupus eritematoso sistêmico e hipotireoidismo, evoluiu com plaquetopenia severa após o uso irregular de sulfametoxazol-trimetoprim. Foi Instituída terapêutica com transfusão de plaquetas, predinisone e pulsoterapia com metil- predinisona. A paciente apresentou resposta clínica tardia, no 26° dia após o início da pulsoterapia, evoluindo, porém, com complicações do tratamento, tais como infecções graves e hiperglicemia.

The patient MLe, 46 years old, female, with SLE and hypothy- roidism, developed important thrombocytopenia after irregular user of sulfonarnide. The treatment with platelets transfusions, predinisone and pulses with methylpredinisolone in high doses was iniriated. The patients demonstrated a late clinical response,at the twenty-sixth day aftes pulses. Complications of the treatment, like severe infections and hyperglicemia, ocurred.