Armin Birner

Peripheral markers of oxidative stress and antioxidative defense in euthymia of bipolar disorder--Gender and obesity effects.

INTRODUCTION Oxidative and nitrosative stress are implicated in the pathogenesis of uni- and bipolar disorder. Herein we primarily sought to characterize markers of oxidative/nitrosative stress during euthymia in adults with bipolar disorder (BD). Oxidative markers were further evaluated in this BD sample in synopsis with excess overweight or obesity and/or comorbid metabolic syndrome (MetS). METHODS Peripheral markers of oxidative stress [i.e. thiobarbituric acid reactive substance, (TBARS), malondialdehyde (MDA), and carbonyl proteins] and antioxidant markers [e.g. total antioxidative capacity (TAC), superoxide dismutase (SOD), glutathione S-transferase (GST)] were obtained in a cohort of euthymic adults with BD (N=113) and compared to healthy controls (CG) (N=78). Additionally, anthropometric measures included the body mass index (BMI) [kg/m(2)], waist and hip circumference [cm], waist-to-hip-ratio (WHR), waist to height ratio (WtHR) as well as the IDF-defined MetS. RESULTS The major finding was a significantly decreased TAC in BD compared to the CG (p<0.01; BD: M 1.18, SD 0.47; CG: M 1.39, SD 0.49). MDA was significantly and TBARS by trend higher in the CG compared to the euthymic bipolar test persons (MDA: p<0.01, BD: M 0.70, SD 0.18; CG: M 0.81, SD 0.25; TBARS: p<0.1, BD: M 0.78, SD 0.28; CG: M 0.76, SD 0.30). The antioxidative enzyme GST was significantly elevated in both patients and controls (BD: M 298.24, SD 133.02; CG: M 307.27 SD 118.18). Subgroup analysis revealed that the CG with concurrent MetS and obesity had significantly elevated TAC when compared to CG without concurrent MetS (p<0.05, no MetS: M 1.33, SD 0.50; MetS: M 1.67, SD 0.32), as well as persons with BD with or without current MetS (no MetS: M 1.18, SD 0.44; MetS: M 1.15, SD 0.49). Significant correlations between GST and anthropometric variables were found in male study participants. Multivariate analysis indicated a significant gender effect concerning TBARS values in all patients and CG (p<0.01, females: M 0.73, SD 0.29; males: M 0.83, SD 0.28). CONCLUSION Euthymic bipolar adults exhibit peripheral evidence of a disturbed biosignature of oxidative stress and antioxidative defense. Male test persons showed significantly higher peripheral markers of oxidative stress than women- female sex may exert protective effects. Furthermore, the biosignature of oxidative stress obtained herein was more pronounced in males with concurrent metabolic disorders. Our results further extend knowledge by introducing the moderating influence of gender and obesity on oxidative stress and BD.

Tryptophan breakdown is increased in euthymic overweight individuals with bipolar disorder: a preliminary report.

Individuals with bipolar disorder (BD) are disproportionately affected by symptoms of being overweight and metabolic syndrome when compared to the general population. The pertinence of this observation is underscored by observations that excess weight is associated with a more complex illness presentation, course, and outcome in BD. We present the first preliminary report of our BIPFAT study, which explored shared hypothesized pathophysiological pathways between being overweight and having BD.

Abdominal obesity is associated with impaired cognitive function in euthymic bipolar individuals

Objectives. Overweight/obesity has been implicated to play a role in cognitive deficits in bipolar disorder (BD). This study aims to identify the relationship between body fat distribution and different domains of cognition in BD during euthymia. Methods. A sample of 100 euthymic individuals with BD was measured with a cognitive test battery (i.e., Trail Making Test-A-B/TM-A/B, d2 Test of Attention, Stroop test, California Verbal Learning Test/CVLT) and an anthropometric measures set (body mass index, waist circumference, hip circumference, waist-to-hip-ratio, waist-to-height-ratio, and lipometry). Patient data were compared with a healthy control group (n = 64). Results. Results show that overweight patients with BD exhibit lower performance in the TMT-A/B as well as in the free recall performance of the CVLT compared to normal-weight patients with BD and controls. In bipolar individuals, (abdominal) obesity was significantly associated with a poor cognitive performance. In bipolar females, associations with measures of verbal learning and memory were found; in bipolar males, associations with poor performance in the TMT-A/B and in the Stroop interference task were demonstrated. In controls, no associations were found. Conclusions. There are several possible pathways moderating the association between obesity and cognition in BD. Anthropometric and lipometry data underline the substantial mediating impact of body fat distribution on cognition in BD.

Weight cycling in bipolar disorder

BACKGROUND An association between excess weight and/or weight fluctuations and cardiovascular morbidity and mortality is amply documented. Individuals with bipolar disorder (BD) are differentially affected by overweight/obesity, chaotic eating patterns (e.g., binge eating), as well as cardiovascular morbidity and mortality. Weight cycling (WCYC) is defined as a pattern of repetitive weight loss and gain. METHODS We sought to determine the relationship between course of illness and BD and WCYC retrospectively as well whether these co-occurring phenotypes identify a biologically distinct subpopulation on the basis of having a unique inflammatory biomarker/biosignature profile. Sociodemographic, clinical, and inflammatory markers were gathered from a well-characterized cohort of actual euthymic adults with BD (n=101) and a healthy control group (n=48). RESULTS Individuals with BD with a history of WCYC were provided evidence of a greater frequency of prior episodes (i.e., both manic and depressed), as well as of significantly higher levels of circulating IL-6 concentrations when compared to non-WCYC individuals with BD. The association persisted after adjusting for relevant covariates (e.g., BMI, age, number of prior episodes). LIMITATIONS Include the small control group, differing medication status and that all data relies on personal information. Nevertheless we tried to verify all data as far as clinical disclosure was available. CONCLUSION The results of this study indicate that adults with BD excessive in weight are not only more susceptible to a relapse-prone course of illness, but also are more likely to present with WCYC. The finding of elevated pro-inflammatory cytokines in this subpopulation may identify a separate subpopulation with greater susceptibility to cardiovascular disease. The overarching aim of personalized treatment and preventive strategies in BD begins with appropriate, empirically supported patient stratification. Our results provide preliminary support for stratifying BD cardiovascular risk on the basis of anthropometrics and WCYC.

Body fat distribution and associations with metabolic and clinical characteristics in bipolar individuals.

Abstract Overweight and obesity differentially affect bipolar disorder (BD) and are associated with a poorer prognosis. Herein, we sought to evaluate body fat distribution in a well-characterized BD sample. Anthropometric measures (i.e., body mass index, waist-to-hip ratio, waist-to-height ratio, waist circumference, hip circumference, and lipometry) of 100 BD individuals were compared with data of 57 matched mentally healthy controls. Additionally, fasting serum parameters including metabolic parameters and monoamines were analyzed. Findings indicate that similar to US BD cohorts, Austrian patients exhibit an increased central body fat accumulation (i.e., higher subcutaneous adipose tissue at upper abdomen) accompanying with the harmful IDF-defined metabolic syndrome. In addition, positive associations between epinephrine as well as staging and fat parameters were detected.

Increased breakdown of kynurenine towards its neurotoxic branch in bipolar disorder

Introduction Bipolar disorder (BD) is a chronic psychiatric disease which can take most different and unpredictable courses. It is accompanied by unspecific brainstructural changes and cognitive decline. The neurobiological underpinnings of these processes are still unclear. Emerging evidence suggests that tryptophan catabolites (TRYCATs), which involve all metabolites of tryptophan towards the kynurenine (KYN) branch, are involved in the etiology as well as in the course of BD. They are proposed to be mediators of immune-inflammation and neurodegeneration. In this study we measured the levels of KYN and its main catabolites consisting of the neurotoxic hydroxykynurenine (3-HK), the more neuroprotective kynurenic acid (KYNA) and anthranilic acid (AA) and evaluated the ratios between end-products and substrates as proxies for the specific enzymatic activity (3-HK/KYN, KYNA/KYN, AA/KYN) as well as 3-HK/KYNA as a proxy for neurotoxic vs. neuroprotective end-product relation in individuals with BD compared to healthy controls (HC). Methods We took peripheral TRYCAT blood levels of 143 euthymic to mild depressive BD patients and 101 HC. For statistical analyses MANCOVA’s controlled for age, sex, body mass index, cardiovascular disease and smoking were performed. Results The levels of KYNA (F = 5,579; p <.05) were reduced in BD compared to HC. The enzymatic activity of the kynurenine-3-monooxygenase (KMO) reflected by the 3-HK/KYN ratio was increased in BD individuals compared to HC (F = 5,394; p <.05). Additionally the ratio of 3-HK/KYNA was increased in individuals with BD compared to healthy controls (F = 11,357; p <.01). Discussion In conclusion our findings subserve the concept of KYN -pathway alterations in the pathophysiology of BD. We present evidence of increased breakdown towards the neurotoxic branch in KYN metabolism even in a euthymic to mild depressive state in BD. From literature we know that depression and mania are accompanied by inflammatory states which should be capable to produce an even greater imbalance due to activation of key enzymes in the neurotoxic direction of KYN -conversion. These processes could finally be involved in the development of unspecific brain structural changes and cognitive deficits which are prevalent in BD. Further research should focus on state dependent changes in TRYCATs and its relation to cognition, brain structure and staging parameters.

Is the molecular clock ticking differently in bipolar disorder? Methylation analysis of the clock gene ARNTL.

Abstract Objectives: The clock gene ARNTL is associated with the transcription activation of monoamine oxidase A according to previous literature. Thus, we hypothesised that methylation of ARNTL may differ between bipolar disorder (BD) and controls. Methods: The methylation status of one CpG island covering the first exon of ARNTL (PS2) and one site in the 5′ region of ARNTL (cg05733463) were analysed in patients with BD (n = 151) versus controls (n = 66). Methylation analysis was performed by bisulphite-conversion of DNA from fasting blood with the EpiTect Bisulfite Kit, PCR and pyrosequencing. Analysis of covariances considering the covariates age, body mass index, sex, smoking, lithium and anticonvulsant intake were performed to test methylation differences between BD and controls. Results: Methylation at cg05733463 of ARNTL was significantly higher in BD than in controls (F(1,209) = 44.500, P < .001). In contrast, methylation was significantly lower in BD at PS2_POS1 compared to controls (F(1,128) = 5.787, P = .018) and by trend at PS2_POS2 (F(1,128) = 3.033, P = .084) and POS7 (F(1,34) = 3.425, P = .073). Conclusions: Methylation of ARNTL differed significantly between BD and controls. Thus, our study suggests that altered epigenetic regulation of ARNTL might provide a mechanistic basis for better understanding circadian rhythms and mood swings in BD.

Mood Stabilizers, Oxidative Stress and Antioxidative Defense in Euthymia of Bipolar Disorder

BACKGROUND Hitherto literature indicates that mood stabilizers exert variable effects on oxidative and antioxidative systems, which are involved in the pathogenesis of Bipolar Disorder. Herein we primarily sought to characterize markers of peripheral oxidative stress during euthymia in adults with Bipolar Disorder under current intake of different mood stabilizers (lithium, anticonvulsants and atypical antipsychotics/AAPs). METHODS Peripheral oxidative stress parameters (TBARS/Thiobarbituric acid-reactive-substances, MDA/ malondialdehyde and carbonyl proteins) and antioxidative markers (SOD/Cu/Zn superoxide dismutase, GST/glutathione Stransferase and TAC/total antioxidative capacity) were measured in serum of 115 euthymic bipolar individuals (50 females, 65 males; HAMD<11 and YMRS<8). Differences in (anti)oxidative markers between bipolar participants treated with different mood stabilizing medication were tested with MANCOVAS and ANCOVAS with SPSS.21. RESULTS Bipolar individuals taking lithium had significantly lower oxidative parameters than test persons without lithium (multivariate effect for MDA and TBARS: F(2/182)= 3.956, p= 0.021; univariate effect for MDA: F(2/182)= 7.880, p= 0.006, Partial η2= 0.041). Subjects with AAPs had significantly higher MDA and TBARS levels compared to participants without AAPs (multivariate effect F(2/182)= 3.122, p= 0.046, Partial η2= 0.033). Patients taking anticonvulsants had significantly lower GST levels than patients without antiepileptic medication (F(1/165)= 4.501, p= 0.035, Partial η2= 0.027). CONCLUSION Lithium taking participants had the lowest MDA and TBARS levels, while AAP taking test persons had high oxidative stress markers. The observed effects on oxidative markers may provide a mechanistic basis for understanding lithiums neuroprotective effects.

Endoplasmic Reticulum Stress and Bipolar Disorder - Almost Forgotten Therapeutic Drug Targets in the Unfolded Protein Response Pathway Revisited

Bipolar Disorder (BD) is characterized by recurring mood swings, which are not completely understood yet. So far, it is an accepted theory that multiple factors contribute to pathogenesis of BD according to the vulnerability-stressmodel. This model combines on the one hand biological predisposing vulnerability, and on the other hand several chronic and acute stressful negative events as underlying mechanisms of BD. Recently, ER (Endoplasmic Reticulum) stress reached the spotlight of BD research again. The expression of the chaperone BiP (syn. GRP78/glucose-regulated protein, 78kDa), which is highly expressed in the Endoplasmic Reticulum (ER), is upregulated by different kinds of mood stabilizers. These results implied that the ER, an organelle which is prone towards different kinds of cellular stress, might be involved in the pathophysiology of BD. This hypothesis was further strengthened by hypothesis driven genetic association studies, which showed significant association of BiP promotor polymorphisms with BD. Also other ER-stress associated genes like XBP1 (X-box binding protein 1) or GRP94 (glucose-regulated protein, 94kDa, synonym for heat shock protein HSP90B1) were recently linked to BD in hypothesis driven gene association studies. In addition to the proteins mentioned before, our review focuses on further UPR (Unfolded Protein Response) related proteins associated with BD and raises the hypothesis that ER-stress may represent a common interface between BD and obesity which is overrepresented in BD patients. Finally, members of the UPR pathway are discussed as putative targets for mood stabilizers.

Cerebral White Matter Lesions and Affective Episodes Correlate in Male Individuals with Bipolar Disorder

Background Cerebral white matter lesions (WML) have been found in normal aging, vascular disease and several neuropsychiatric conditions. Correlations of WML with clinical parameters in BD have been described, but not with the number of affective episodes, illness duration, age of onset and Body Mass Index in a well characterized group of euthymic bipolar adults. Herein, we aimed to evaluate the associations between bipolar course of illness parameters and WML measured with volumetric analysis. Methods In a cross-sectional study 100 euthymic individuals with BD as well as 54 healthy controls (HC) were enrolled to undergo brain magnetic resonance imaging using 3T including a FLAIR sequence for volumetric assessment of WML-load using FSL-software. Additionally, clinical characteristics and psychometric measures including Structured Clinical Interview according to DSM-IV, Hamilton-Depression, Young Mania Rating Scale and Beck’s Depression Inventory were evaluated. Results Individuals with BD had significantly more (F = 3.968, p < .05) WML (Mdn = 3710mm3; IQR = 2961mm3) than HC (Mdn = 2185mm3; IQR = 1665mm3). BD men (Mdn = 4095mm3; IQR = 3295mm3) and BD women (Mdn = 3032mm3; IQR = 2816mm3) did not significantly differ as to the WML-load or the number and type of risk factors for WML. However, in men only, the number of manic/hypomanic episodes (r = 0.72; p < .001) as well as depressive episodes (r = 0.51; p < .001) correlated positively with WML-load. Conclusions WML-load strongly correlated with the number of manic episodes in male BD patients, suggesting that men might be more vulnerable to mania in the context of cerebral white matter changes.