Pamela Ferrari

Hypothalamic-pituitary-adrenal axis dysfunction and illness progression in bipolar disorder.

Background: Impaired stress resilience and a dysfunctional hypothalamic-pituitary-adrenal (HPA) axis are suggested to play key roles in the pathophysiology of illness progression in bipolar disorder (BD), but the mechanisms leading to this dysfunction have never been elucidated. This study aimed to examine HPA axis activity and underlying molecular mechanisms in patients with BD and unaffected siblings of BD patients. Methods: Twenty-four euthymic patients with BD, 18 siblings of BD patients, and 26 healthy controls were recruited for this study. All subjects underwent a dexamethasone suppression test followed by analyses associated with the HPA axis and the glucocorticoid receptor (GR). Results: Patients with BD, particularly those at a late stage of illness, presented increased salivary post-dexamethasone cortisol levels when compared to controls (p = 0.015). Accordingly, these patients presented reduced ex vivo GR responsiveness (p = 0.008) and increased basal protein levels of FK506-binding protein 51 (FKBP51, p = 0.012), a co-chaperone known to desensitize GR, in peripheral blood mononuclear cells. Moreover, BD patients presented increased methylation at the FK506-binding protein 5 (FKBP5) gene. BD siblings presented significantly lower FKBP51 protein levels than BD patients, even though no differences were found in FKBP5 basal mRNA levels. Conclusions: Our data suggest that the epigenetic modulation of the FKBP5 gene, along with increased FKBP51 levels, is associated with the GR hyporesponsiveness seen in BD patients. Our findings are consistent with the notion that unaffected first-degree relatives of BD patients share biological factors that influence the disorder, and that such changes are more pronounced in the late stages of the illness.

Effects of a single bout of maximal aerobic exercise on BDNF in bipolar disorder: A gender-based response

Acute exercise increases brain-derived neurotrophic factor (BDNF) serum levels in majorly depressed and anxious patients. However, to the best of our knowledge, no study has evaluated the acute effects of exercise on BDNF serum levels in Bipolar Disorder (BD). The objective of the present study was to evaluate the peripheral BDNF serum response to a single maximum session of exercise in BD participants and age- and gender-matched healthy participants. BD participants (n=18) and age- and gender-matched healthy participants (n=18) were recruited to perform a single bout of maximal exercise on a cycle ergometer. Blood samples were collected prior to and immediately after the exercise protocol. There was a significant group effect and a significant group x time x gender interaction. BD participants presented significantly higher BDNF serum levels when compared to their healthy control counterparts. Exercise increases the BDNF levels of BD women, but not men.

Serum concentrations of brain-derived neurotrophic factor in patients with gender identity disorder

Gender Identity Disorder (GID) is characterized by a strong and persistent cross-gender identification that affects different aspects of behavior. Brain-derived neurotrophic factor (BDNF) plays a critical role in neurodevelopment and neuroplasticity. Altered BDNF-signaling is thought to contribute to the pathogenesis of psychiatric disordersand is related to traumatic life events. To examine serum BDNF levels, we compared one group of DSM-IV GID patients (n = 45) and one healthy control group (n = 66). Serum BDNF levels were significantly decreased in GID patients (p = 0.013). This data support the hypothesis that the reduction found in serum BDNF levels in GID patients may be related to the psychological abuse that transsexuals are exposed during their life.

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

Abstract 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.

Elevated serum protein oxidative stress in siblings of patients with schizophrenia.

Fig. 1. (A) Serum levels of protein carbonyl content (PCC), (B) Thiobarbituric acid-reactive substance (TBARS) levels and (C) glutathione peroxidase (GPx) in siblings of patients with schizophrenia comparedwith healthy controls. Horizontal lines indicate median in (A) and (B). In (C) thehorizontal line indicates themean. Data points show individual values. Statistical significance is given by the indicated p value. A and B were analyzed using Mann– Whitney test. C was analyzed using t-test. Elevated serum protein oxidative stress in siblings of patients with schizophrenia

BDNF: a biomarker for social vulnerability in individuals diagnosed with gender dysphoria.

Fuss and colleagues discussed in a review the role of brainderived neurotrophic factor (BDNF) in gender identity disorder, now gender dysphoria (GD) (Fuss et al., 2013). In this work, the authors highlighted some aspects of our article (Fontanari et al., 2013) stating that we conclude that BDNF might be a biomarker for GD. We thank Fuss and colleagues for emphasizing important topics of our article. However, we do not agree with some of their assessments. By comparing a group of GD patients (n 1⁄4 45) with a control group (n 1⁄4 66), our study found that the serum BDNF levels were significantly decreased in individuals diagnosed with GD (Fontanari et al., 2013). Decreased serum BDNF levels were also associatedwith childhood traumatic events in patients with bipolar disorder (BD) (Kauer-Sant’Anna et al., 2007). In this study, Kauer-

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-1β (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.