Barbara T. Santos

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.

Early apoptosis in peripheral blood mononuclear cells from patients with bipolar disorder

BACKGROUND The pathophysiology of bipolar disorder (BD) includes several systemic alterations, such as inflammatory markers, oxidative stress, and DNA damage. Most of these parameters may be related to dysfunctions in cellular resilience mechanisms reported in patients, such as endoplasmic reticulum stress and mitochondrial damage. As a consequence, these impairments can ultimately lead to cell death. Therefore, the aim of this study was to assess cell death and viability in peripheral blood mononuclear cells (PBMCs) from patients with BD and controls. METHODS Ten euthymic patients with BD type I and seven age- and sex-matched healthy controls were recruited and had peripheral blood collected by venipuncture in heparine tubes. PBMCs were isolated from total blood, followed by measurement of cell viability by trypan blue exclusion, and apoptosis and necrosis by anexin V/propidium iodide (PI) staining. RESULTS Cell viability did not significantly differ between groups, as well as the percentage of cells in necrosis or in late apoptosis/necrosis. However, the percentage of cells in early apoptosis was higher in patients when compared with controls (p=0.002). LIMITATIONS This is a preliminary study with relatively small sample size. CONCLUSIONS The systemic toxicity along with dysfunctional cell resilience mechanisms reported in patients with BD may be inducing apoptosis in PBMCs. A deeper look into the clinical relevance of such findings is warranted.

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.

Verbal memory impairment in healthy siblings of patients with schizophrenia

Cognitive deficits have been recognized as a core feature of schizophrenia (SZ) and are present in most patients. Verbal memory (VM), working memory (WM), and executive function (EF) are domains commonly impaired in patients with SZ. These latter domains have been related to the genetic risk of the disorder characterizing as possible endophenotypes. In order to study neurocognitive endophenotypes in a Brazilian population with elevated genetic risks to develop SZ, we measured VM (Hopkins Verbal Learning Test Revised), WM (Letter-Number Sequencing and Digit Span) and EF (Stroop Test) in 90 subjects (45 unaffected siblings of patients with SZ and 45 matched healthy controls). No differences were found in EF and WM (Letter-Number Sequencing and Digit Span). However, in VM, siblings of patients performed worse than controls on the immediate recall and delayed recall. Our results suggest that VM impairment could be considered an endophenotype of SZ.

Cognitive performance and psychosocial functioning in patients with bipolar disorder, unaffected siblings, and healthy controls

Objective: To assess cognitive performance and psychosocial functioning in patients with bipolar disorder (BD), in unaffected siblings, and in healthy controls. Methods: Subjects were patients with BD (n=36), unaffected siblings (n=35), and healthy controls (n=44). Psychosocial functioning was accessed using the Functioning Assessment Short Test (FAST). A sub-group of patients with BD (n=21), unaffected siblings (n=14), and healthy controls (n=22) also underwent a battery of neuropsychological tests: California Verbal Learning Test (CVLT), Stroop Color and Word Test, and Wisconsin Card Sorting Test (WCST). Clinical and sociodemographic characteristics were analyzed using one-way analysis of variance or the chi-square test; multivariate analysis of covariance was used to examine differences in neuropsychological variables. Results: Patients with BD showed higher FAST total scores (23.90±11.35) than healthy controls (5.86±5.47; p < 0.001) and siblings (12.60±11.83; p 0.001). Siblings and healthy controls also showed statistically significant differences in FAST total scores (p = 0.008). Patients performed worse than healthy controls on all CVLT sub-tests (p < 0.030) and in the number of correctly completed categories on WCST (p = 0.030). Siblings did not differ from healthy controls in cognitive tests. Conclusion: Unaffected siblings of patients with BD may show poorer functional performance compared to healthy controls. FAST scores may contribute to the development of markers of vulnerability and endophenotypic traits in at-risk populations.