Izabela Guimarães Barbosa

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.

Increased serum levels of brain-derived neurotrophic factor in chronic institutionalized patients with schizophrenia.

There is a growing body of evidence implicating the neurotrophin brain-derived neurotrophic factor (BDNF) in the pathogenesis of schizophrenia. As circulating BDNF levels may reflect the BDNF levels in the brain, we assessed serum BDNF in 40 institutionalized schizophrenic patients and 20 healthy controls. Serum BNDF levels were significantly increased in schizophrenic patients when compared to control subjects (p<0.001). Interestingly, serum BDNF correlated positively with the clinical scores at the negative subscale of the positive and negative syndrome scale (PANSS) (r=0.41; p<0.01). Our results confirm the emergent literature on the involvement of BDNF in schizophrenia.

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.

The immunology of bipolar disorder.

Bipolar disorder (BD) is a psychiatric condition associated with elevated frequency of clinical comorbidities and cognitive impairment. The neurobiology of BD is not completely understood. Recent evidence has implicated immune dysfunction in its physiopathology. Here, we review several data supporting the presence of immunological dysfunction in BD: (i) increased frequency of autoimmune diseases; (ii) distinct immune cell profile; (iii) release of/altered cytokines by stimulated mononuclear cells; (iv) elevated levels of circulating immune markers, and (v) inflammatory changes in the central nervous system. We also discuss the interplay between immunological dysfunction and neuroprogression in BD.

Insufficient glucocorticoid signaling and elevated inflammation in coronary heart disease patients with comorbid depression

Coronary heart disease (CHD) and depression are very common and often co-existing disorders. In addition to psychological and social morbidity, depression exacerbates adverse cardiac outcomes in CHD patients. Inflammation has been proposed as one of the mechanisms involved in the association between these two debilitating diseases. Therefore, the present study aimed to evaluate inflammatory responses as well as to investigate the pathophysiological mechanisms underlying the putative inflammatory activation in CHD patients with and without depression, by assessing the function of two important biological factors regulating inflammation, the hypothalamus-pituitary-adrenal (HPA) axis and the glucocorticoid receptor (GR). Eighty-three CHD patients with (n=28) and without (n=55) comorbid depression were recruited from primary care services in South London. Depression status was assessed by means of Clinical Interview Schedule Revised for diagnosis of depression, and Beck Depression Inventory for the presence of depressive symptoms. Serum C-reactive protein (CRP), plasma vascular endothelial growth factor (VEGF), and plasma and salivary cortisol were measured using commercially available ELISA kits. Gene expression of GR and interleukin-6 (IL-6) were conducted via qPCR. GR sensitivity was evaluated in vitro in isolated peripheral blood mononuclear cells using the dexamethasone inhibition of lipopolysaccharide-stimulated IL-6 levels. Serum levels of kynurenine pathway metabolites were measured using high performance liquid chromatography. Our results show that CHD patients with depression had higher levels of CRP, IL-6 gene expression, and VEGF compared with CHD non-depressed, as well as lower plasma and saliva cortisol levels. The CHD depressed group also exhibited a reduction in GR expression and sensitivity. Finally, tryptophan levels were significantly lower in patients with depression, who also showed an increased kynurenine/tryptophan ratio. In conclusion, CHD patients with depression had elevated levels of inflammation in the context of HPA axis hypoactivity, GR resistance, and increased activation of the kynurenine pathway. Reduced cortisol bioavailability and attenuated glucocorticoid responsiveness due to decreased expression and sensitivity of GR may lead to insufficient glucocorticoid signaling and thus elevation of inflammation in these patients.

Cytokines in Bipolar Disorder: Paving the Way for Neuroprogression

Bipolar disorder (BD) is a severe, chronic, and recurrent psychiatric illness. It has been associated with high prevalence of medical comorbidities and cognitive impairment. Its neurobiology is not completely understood, but recent evidence has shown a wide range of immune changes. Cytokines are proteins involved in the regulation and the orchestration of the immune response. We performed a review on the involvement of cytokines in BD. We also discuss the cytokines involvement in the neuroprogression of BD. It has been demonstrated that increased expression of cytokines in the central nervous system in postmortem studies is in line with the elevated circulating levels of proinflammatory cytokines in BD patients. The proinflammatory profile and the immune imbalance in BD might be regarded as potential targets to the development of new therapeutic strategies.

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.

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.

Impaired nerve growth factor homeostasis in patients with bipolar disorder

Abstract 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.

Neurotrophic factors in obsessive-compulsive disorder

In this cross-sectional study, we assessed the levels of neurotrophins (NF) of patients with obsessive-compulsive disorder (OCD) in different stages of treatment and their relationship with OCD clinical features. Forty patients with OCD and 40 healthy controls had Brain-Derived Neurotrophic Factor (BDNF), Nerve Growth Factor (NGF), and Glial Cell-Derived Neurotrophic Factor (GNDF) plasma levels measured by enzyme-linked immunosorbent assay (ELISA). Patients with OCD were further examined with the Obsessive-Compulsive Inventory-Revised, the Beck Depression Inventory, the Beck Anxiety Inventory, and the Sheehan Disability Scale (SDS). Patients with OCD exhibited significantly lower levels of BDNF and significantly increased levels of NGF as compared to healthy controls. In OCD, statistically significant negative correlations between BDNF levels and number of working days lost per week were found. Additional analyses revealed a statistically significant positive correlation between both NGF and GDNF and severity of washing symptoms. Plasma levels of NF were not affected by age, age at OCD onset, gender, major depressive disorder, the relative dose of serotonin-reuptake inhibitors being prescribed, or the use of antipsychotics. Our findings suggest that patients with OCD may exhibit a particular NF profile, with functional impairment correlating with BDNF levels and severity of washing symptoms correlating with NGF and GDNF levels.