Sebastian Rudolf

S100B and response to treatment in major depression: a pilot study

S100B is a protein which exerts both detrimental and neurotrophic effects, depending on its concentration in brain tissue. An increase of S100B in micromolar concentrations is observed in traumatic brain conditions and is associated with poor outcome. Micromolar levels of extracellular S100B in vitro may have deleterious effects. However, in nanomolar concentrations S100B has multiple neurotrophic effects in vitro may in vivo be regarded as a hallmark of neuroprotective efforts. This pilot study addresses the hypothesis that S100B serum concentrations may be of predictive validity for the response to antidepressant treatment in patients with major depression. S100B plasma levels were determined in 25 patients with major depression and 25 matched healthy controls using an immunofluorimetric sandwich assay. S100B plasma levels were significantly higher in major depressive patients than in healthy controls and positively correlated with treatment response after 4 weeks of treatment. In a linear regression model, a significant predictive effect was found only for S100B and severity of depressive symptoms upon admission. These results suggest that neuroprotective functions of S100B counterbalance neurodegenerative mechanisms that are involved in the pathophysiology of major depression and in the response to antidepressant treatment.

S-100B is increased in melancholic but not in non-melancholic major depression

BACKGROUND Recent evidence suggests that neurodegeneration may be involved in the pathophysiology of major depression. The astroglial peptide S-100B was shown to be increased in many diseases causing neuronal cell damage or degeneration. METHOD S-100B plasma levels were determined in 28 patients with major depression and 28 matched healthy controls using an immunofluorometric sandwich assay. RESULTS Patients suffering from melancholic depression showed significantly increased S-100B levels compared to healthy controls while non-melancholic patients demonstrated normal levels. LIMITATIONS Medication of patients varied. The differentiation between melancholic and non-melancholic patients was performed clinically without using a standardized instrument. CONCLUSIONS Neurodegeneration or axonal remodeling may be involved in the pathogenesis of melancholic depression.

Angiogenic factors in patients with current major depressive disorder comorbid with borderline personality disorder

BACKGROUND Major depression has been associated with endocrine and immune alterations, in particular a dysregulation of the hypothalamus-pituitary-adrenal system with subsequent hypercortisolism and an imbalance of pro- and anti-inflammatory cytokines. Recent studies suggest that vascular endothelial growth factor (VEGF), a cytokine involved in angiogenesis and neurogenesis, may also be dysregulated during stress and depression. These observations prompted us to examine VEGF and other angiogenic factors in patients with major depressive disorder. METHODS Twelve medication-free female patients with a major depressive episode in the context of borderline personality disorder (MDD/BPD) and twelve healthy women were included. Concentrations of VEGF, VEGF receptors 1 and 2, basic fibroblast growth factor-2 (FGF-2), hepatocyte growth factor (HGF), angiopoetin-2, interleukin-8 (IL-8) and transforming growth factor-beta1 (TGF-beta1) were determined from serum profiles. RESULTS Increased concentrations of VEGF and FGF-2 were found in MDD/BPD patients compared to the healthy comparator group. No group differences were found concerning the other angiogenic factors examined. CONCLUSION Depressive episodes in the context of borderline personality disorder may be accompanied by increased serum concentrations of VEGF and FGF-2. Similar findings have been observed in patients with major depression without a borderline personality disorder. A dysregulation of angiogenic factors may be another facet of the endocrine and immunologic disturbances frequently seen in patients with depressive episodes.

Cortisol, the Cortisol-Dehydroepiandrosterone Ratio, and Pro-Inflammatory Cytokines in Patients with Current Major Depressive Disorder Comorbid with Borderline Personality Disorder

BACKGROUND Major depression in young women is often comorbid with borderline personality disorder (BPD); however, adrenal steroids and pro-inflammatory cytokines in patients with comorbid current major depressive disorder and BPD (MDD/BPD) have not been systematically examined. Therefore, our study aimed at examining serum profiles of cortisol, cytokines, and the cortisol/dehydroepiandrosterone (cortisol/DHEA) ratio in MDD/BPD patients and a healthy comparison group. METHODS Twelve medication-free female patients with MDD/BPD and 12 healthy women were included. Serum profiles of cortisol, DHEA, tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), and interleukin-1beta were sampled, and the molar cortisol/DHEA ratio was determined. RESULTS Concentrations of serum cortisol, TNF-alpha, and IL-6, as well as the cortisol/DHEA ratios were significantly increased in MDD/BPD patients as compared with the healthy comparison group. CONCLUSIONS Depressed patients with comorbid BPD display endocrine and immune alterations similar to those observed in cases of melancholic MDD without BPD. Elevated concentrations of serum cortisol, cortisol/DHEA ratios, and pro-inflammatory cytokines might indicate a state marker in these patients and might contribute to long-term metabolic alterations that have also been associated with MDD.

Visceral fat deposition and insulin sensitivity in depressed women with and without comorbid borderline personality disorder.

Objective: Major depressive disorder (MDD) is associated with increased intra-abdominal fat, an important antecedent of noninsulin-dependent diabetes mellitus (NIDDM) and cardiovascular disorders. Furthermore, MDD is commonly accompanied by endocrine and immune dysregulation that has also been discussed in connection with the pathogenesis of NIDDM and ischemic heart disease. In borderline personality disorder (BPD), a dysregulation of the hypothalamic–pituitary–adrenal system has also been described. Therefore, our study aimed at examining visceral fat, insulin resistance, and alterations of cortisol and cytokines in young depressed women with and without comorbid BPD. Methods: Visceral fat was measured in 18 premenopausal women with MDD and in 18 women comorbid with MDD and BPD by means of magnetic resonance tomography at the level of the first lumbar vertebral body. Twelve BPD patients without MDD and 20 healthy women served as the comparison groups. Concentrations of fasting cortisol, tumor necrosis factor-&agr;, and interleukin-6 were measured, and indicators of insulin resistance and &bgr;-cell sensitivity were calculated according to the homeostasis assessment model. Results: We found increased visceral fat in women comorbid with MDD and BPD, and to a lesser extent, in women with MDD but without BPD. Insulin sensitivity was reduced in comorbid patients. Serum interleukin-6 (IL-6) and tumor necrosis factor-&agr; concentrations were significantly increased in both groups of depressed patients. Reduced insulin sensitivity correlated with the amount of visceral fat and with serum concentrations of IL-6. Conclusion: Young depressed women with and without comorbid BPD display increased visceral fat and may constitute a risk group for the development of NIDDM and the metabolic syndrome. Our data support the hypothesis that the immune and endocrine alterations associated with MDD and BPD may contribute to the pathophysiologic processes associated with NIDDM. BMI = body mass index; BPD = borderline personality disorder; ES = effect size; HOMA = homeostasis model assessment (-IR: insulin resistance; −S: &bgr;-cell sensitivity); IL-6 = interleukin-6; MDD = major depressive disorder; NIDDM = noninsulin-dependent diabetes mellitus; TNF-&agr; = tumor necrosis factor-&agr;; VF/L = visceral fat at the level of the first lumbar vertebral body (VF/L1-: 10 mm below L1; VF/L1+ = 10 mm above L1).

Bone mineral density, bone turnover, and osteoprotegerin in depressed women with and without borderline personality disorder.

Objective: Low bone mineral density has repeatedly been reported in patients with major depressive disorder (MDD), and MDD has been discussed as a risk factor for the development of osteoporosis. MDD in young adults often occurs in the context of borderline personality disorder (BPD), and both MDD and BPD have been associated with a dysregulation of the hypothalamic–pituitary–adrenal system and subsequent hypercortisolemia. To date, it is unclear whether comorbid BPD in depressed patients modulates the extent of bone mass reduction. Therefore, we examined bone density, markers of bone turnover, and proinflammatory cytokines in depressed patients with and without BPD. Patients with BPD alone and healthy women served as comparison groups. Method: Twenty-four patients with MDD and 23 patients with comorbid MDD and BPD were included. Sixteen patients with BPD and 20 healthy women of similar body mass index served as the comparison group. BMD was assessed by means of dual-energy x-ray absorptiometry. Markers of bone turnover, endocrine and immune parameters were determined. For data analysis, the group of depressed patients without comorbid BPD was divided according to age into two groups (younger depressed patients with a mean age of 30 years and older patients with a mean age of 42.9 years). Results: BMD at the lumbar spine was significantly reduced in a) depressed women with comorbid BPD (mean age, 28.6 years) and in b) older depressed patients without BPD (mean age, 42.9 years). Osteocalcin, a marker of osteoblastic activity, and crosslaps, a marker of bone loss, were significantly different between the study groups. Tumor necrosis factor-α was increased in depressed patients when compared with healthy women. Furthermore, TNF-α was positively correlated with serum crosslaps, a marker for osteoclastic activity. Conclusion: Depression is associated with reduced bone mass, in particular in patients with comorbid BPD. Possible factors contributing to BMD reduction include endocrine and immune alterations associated with either MDD or BPD. We conclude from our data that a history of MDD with and without comorbid BPD should be considered as a risk factor in clinical assessment instruments for the identification of persons prone to osteoporosis. BPD = borderline personality disorder; BMD = bone mineral density; AP = lumbar spine; RF = right femur; LF = left femur; FA = forearm; BMI = body mass index; HPAS = hypothalamic–pituitary–adrenal system; IGF-I = insulin-like growth factor-I; IL-6 = interleukin-6; MDD30 = patients with major depressive disorder and a mean age of 30 years; MDD43 = patients with major depressive disorder and a mean age of 43 years; MDD/BPD = patients with comorbid major depressive disorder and borderline personality disorder; OPG = osteoprotegerin; PTH = parathormone; TNF-α = tumor-necrosis factor-α.

Cytokine production in unmedicated and treated schizophrenic patients.

Recent findings have strengthened the hypothesis that immunological dysfunctions may contribute towards the multifactorial pathogenesis of schizophrenia. The validity of these findings is questioned by the fact that most studied subjects have received potentially immunomodulatory medication upon investigation. In order to rule out such confounding effects, 24 initially unmedicated acutely ill schizophrenic patients were studied immunologically and psychiatrically (PANSS) before and during 4 weeks of neuroleptic treatment. The production of IFN-γ was decreased upon admission and after 2 weeks of treatment compared to matched healthy controls. No differences in IL-2 and IFN-γ production between unmedicated and medicated states were observed. These results do not support the notion that neuroleptic medication in vivo might influence TH1 cytokine production in schizophrenia.

Disturbed glucose disposal in patients with major depression; application of the glucose clamp technique.

Objective: To assess the whole-body glucose disposal in patients with both typical and atypical depression and to characterize the neuroendocrine responses during a hyper-, eu-, hypoglycemic stepwise clamp experiment in patients with both subtypes of major depression. Depressive disorders and alterations in glucose metabolism are closely associated. The glucose clamp technique is considered to be the “gold standard” for the assessment of whole-body glucose disposal. Methods: We studied 19 patients with typical major depressive disorder (MDD), 7 patients with atypical major depression, and 30 men and women of a healthy comparator group using a stepwise glucose clamp procedure. Glucose disposal rates were assessed and concentrations of hormones involved in glucose allocation were measured. Results: Glucose disposal rates were lower by 19% in patients with typical MDD and 30% in patients with atypical MDD than in the group of healthy controls (3.2 ± 0.8 and 2.8 ± 0.7 versus 4.0 ± 1.0 mmol h−1 kg−1). C-peptide concentrations were 26% higher in patients with atypical MDD and similar in patients with typical MDD and healthy controls. Vascular endothelial growth factor concentrations were 30% higher in typical MDD and similar in atypical MDD and the control group. Conclusions: Whole-body glucose disposal is reduced in patients with typical and atypical depression. The observed neuroendocrine responses suggest a hyperactive allocation system in typical depression and a hypoactive allocation system in atypical depression. ACTH = adrenocorticotropic hormone; ANOVA = analysis of variance; BMI = body mass index; CV = coefficient of variation; DSM-IV = Diagnostic and Statistical Manual of Mental Disorders, version IV; GH = growth hormone; GLUT1 = glucose transporter Type 1; GLUT4 = glucose transporter Type 4; HDL = high-density lipoproteins; HPA = hypothalamic-pituitary-adrenal; MDD = major depressive disorder; SCID = Structured Clinical Interview for DSM-IV; VEGF = vascular endothelial growth factor.

Elevated IL-6 levels in patients with atypical depression but not in patients with typical depression

Elevated levels of the proinflammatory cytokine Interleukin-6 (IL-6) are among the most consistent findings in patients with major depressive disorder (MDD). Additionally, some evidence suggests that elevated cytokine levels in patients with major depression are responsible for the development of metabolic syndrome in patients suffering from MDD. Therefore, the aim of the study was to examine the concentrations of IL-6 in specific subtypes of MDD and to investigate their relationship to metabolic factors. Twenty-four patients with typical (24) and atypical (eight) major depression according to DSM-IV criteria were studied and compared to 24 normal controls. Blood samples were collected during a stepwise glucose-clamp procedure, and IL-6 concentrations were measured by high sensitivity ELISA. IL-6 levels were elevated in patients suffering from atypical depression but not in patients with typical depression, compared to normal controls. IL-6 correlated significantly with HbA1c, insulin, waist girth, BMI, number of alcoholic drinks per week and C-reactive protein. Our data indicate that high concentrations of IL-6 during the glucose clamp may be limited to the atypical subgroup of patients with MDD.

Decreased osteoprotegerin and increased bone turnover in young female patients with major depressive disorder and a lifetime history of anorexia nervosa

Low bone mineral density (BMD) is a frequent, often persistent complication in patients with major depressive disorder (MDD) and anorexia nervosa (AN) that increases the risk of pathologic fractures. The pathogenetic process underlying osteopenia in MDD and AN is still unclear, although several factors, including a dysbalance of cytokines, are associated with loss of bone mass. Alterations in the serum levels of cytokines have been observed in patients with MDD, AN, and other psychiatric disorders. Therefore, we examined serum levels of cytokines, markers of bone turnover, and BMD in 13 patients with MDD and a lifetime history of AN. Bone turnover markers (osteocalcin and C-terminal degradation products of type I collagen) and tumor necrosis factor α (TNF-α) in patients were significantly increased compared with those of the control group. Osteoprotegerin (OPG) in patients was significantly decreased. Eight of 13 patients (62%) displayed osteopenia at the lumbar spine. TNF-α correlated significantly with C-terminal degradation products of type I collagen, an osteoclastic marker, but significantly negatively with OPG. Our data suggest that TNF-α and OPG may play a role in the pathogenetic process underlying osteopenia in these patients.