Robert Queissner

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.

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.

Extracellular matrix proteins matrix metallopeptidase 9 (MMP9) and soluble intercellular adhesion molecule 1 (sICAM-1) and correlations with clinical staging in euthymic bipolar disorder.

Matrix metallopeptidase 9 (MMP9) and soluble intercellular adhesion molecule 1 (sICAM‐1) are both involved in the restructuring of connective tissues. Evidence also implicates MMP9 and sICAM in cardiovascular and neoplastic diseases, where blood levels may be a marker of disease severity or prognosis. In individuals with bipolar disorder (BD), higher risk for cardiovascular illness has been extensively reported.

The relationship between inflammatory state and quantity of affective episodes in bipolar disorder

OBJECTIVES Immunological/inflammatory processes have been proposed to play an important role in the pathophysiology of mood disorders, including bipolar disorder (BD). The present study aimed to examine the influence of immune activation, measured on the basis of inflammatory markers, on the course of illness, proxied by the number of affective episodes, in patients with BD. METHODS We investigated the relationship between high-sensitive CRP (hsCRP) and Interleukin 6 (IL-6), two inflammatory markers and characteristics of course of illness (e.g. number of affective episodes, depressive and manic symptoms) amongst a group of 190 individuals with BD. RESULTS Among females with BD, there was a positive correlation between levels of hsCRP and the number of manic and depressive episodes. Moreover, levels of hsCRP and IL-6 were positively correlated with current manic symptoms, as measured by Young-Mania-Rating-Scale. There were no significant correlations between levels of the foregoing inflammatory markers, and manic and depressive symptoms in male individuals with BD. Furthermore, compared to their untreated counterparts, female patients treated with lithium demonstrated higher levels of hsCRP and male patients treated with atypical antipsychotics lower levels of hsCRP, respectively. CONCLUSIONS Our results are suggesting that the association between inflammatory state and affective response in patients with BD may be gender-dependent. A future research would be to evaluate whether or not these gender differences can be observed in other inflammatory pathways associated with BD.

Tryptophan breakdown and cognition in bipolar disorder

INTRODUCTION It has been demonstrated that bipolar disorder (BD) is often accompanied by cognitive deficits across all subdomains including verbal memory, attention and executive functioning. Cognitive deficits are observed both during episodes of mania or depression, as well as during the euthymic phase. It has been proposed that chronic immune-mediated inflammation in the central nervous system results in alterations in neural structures that subserve cognitive function. Kynurenine is an intermediate in the inflammatory cascade and can be peripherally measured to proxy inflammatory activity. Herein, we sought to determine whether serum levels of kynurenine and/or its metabolites were associated with cognitive function in BD. METHODS In this investigation 68 euthymic individuals with BD according to DSM-IV completed a cognitive test battery to asses premorbid intelligence (Multiple Choice Word Test; MWT-B), verbal memory (California Verbal Learning Test; CVLT), attention (d2 Test of Attention; d2 test, Trail Making Test-A; TMT-A, Stroop word reading/Stroop color naming) and executive functioning (TMT-B, Stroop interference). In addition, fasting blood samples were taken and serum levels of kynurenine and its metabolites 3-hydroxykynurenine and kynurenic acid were analyzed. Subsequently ratios were formed from individual parameters. Patient data were compared with those of a mentally healthy control group (n=93). RESULTS In male participants with BD only we found a significant negative correlation between the 3-hydroxykynurenine to kynurenic acid ratio and performance on the CVLT. Additionally, the kynurenine to 3-hydroxykynurenine ratio was associated with performance on a sub-score of the CVLT. Those associations were neither present in female individuals with BD nor in the control group. DISCUSSION Our findings suggest that a shift towards the hydroxykynurenine arm of the kynurenine pathway may be associated with poorer memory performance due to its effects on neuronal functioning and neurogenesis in the hippocampus. Our results implicate a mechanistic role of central inflammatory processes in cognitive functions in adults with bipolar disorder.

Adiponectin is decreased in bipolar depression

Abstract Objectives: Bipolar disorder (BD) is often accompanied by medical comorbidities, which affect illness course and prognosis. Adipokines may not only be involved in the aetiopathogenetic mechanisms of these comorbidities; there might be an association between adipokines and the neuropsychiatric core features of BD such as mood disturbances and cognitive deficits. Methods: In this investigation, fasting blood samples from 120 individuals with BD (75 euthymic and 45 with mild depressive symptoms) and 68 control subjects were taken and adiponectin and leptin concentrations were analysed. Results: We found that, in female participants, adiponectin levels differed significantly between patients and controls indicating lower levels in individuals with BD, even after controlling for BMI (F(1,92) = 4.65, P = 0.034, partial η2 = 0.05). After stratification by mood status we found a significant difference in adiponectin between controls, euthymic and depressive patients (F(2, 180) = 4.90, P = 0.008, partial η2 = 0.05). Conclusions: This investigation confirms previous findings of an association between low adiponectin levels and depressive state in individuals with BD. Beyond its immediate effect on central nervous system function, adiponectin might interfere with pathophysiological mechanisms of BD and its somatic comorbidities via involvement in metabolic and inflammatory processes.

Branched-chain amino acids are associated with metabolic parameters in bipolar disorder

Abstract Objectives: An important aspect of bipolar disorder (BD) research is the identification of biomarkers pertaining to the somatic health state. The branched-chain essential amino acids (BCAAs), viz valine, leucine and isoleucine, have been proposed as biomarkers of an individual’s health state, given their influence on protein synthesis and gluconeogenesis inhibition. Methods: BCAA levels of 141 euthymic/subsyndromal individuals with BD and 141 matched healthy controls (HC) were analysed by high-pressure lipid chromatography and correlated with clinical psychiatric, anthropometric and metabolic parameters. Results: BD and HC did not differ in valine and isoleucine, whereas leucine was significantly lower in BD. Furthermore, correlations were found between BCAAs and anthropometric and glucose metabolism data. All BCAAs correlated with lipid metabolism parameters in females. There were no associations between BCAAs and long-term clinical parameters of BD. A negative correlation was found between valine and Hamilton Depression-Scale, and Beck Depression Inventory II, in male individuals Conclusions: Our results indicate the utility of BCAAs as biomarkers for the current state of health, also in BD. As BD individuals have a high risk for overweight/obesity, in association with comorbid medical conditions (e.g. cardiovascular diseases or insulin resistance), health state markers are urgently required. However, no illness-specific associations were found in this euthymic/subsyndromal BD group.

Endoplasmic reticulum stress in bipolar disorder? – BiP and CHOP gene expression- and XBP1 splicing analysis in peripheral blood

BACKGROUND Endoplasmic Reticulum stress activates the Unfolded Protein Response, which is partially impaired in Bipolar Disorder (BD) according to previous in-vitro studies. Thus, BiP and CHOP gene expression and XBP1 splicing were analyzed in peripheral blood of study participants with BD and controls. METHODS RNA was isolated from fasting blood of study participants with BD (n = 81) and controls (n = 54) and reverse transcribed into cDNA. BiP and CHOP gene expression was analyzed with quantitative RT-PCR. Atypical splicing of XBP1 mRNA was measured by semi-quantitative RT-PCR, gel-electrophoresis and densitometry. ANCOVAs with the covariates age, BMI, sex, lithium and anticonvulsants intake were used with SPSS. Bonferroni correction was used to correct for multiple testing (adjusted p = 0.0083). RESULTS BiP gene expression was significantly higher in BD than in controls (F(1/128) = 10.076, p = 0.002, Partial η2 = 0.073). Total XBP1 (F(1/126) = 9.550, p = 0.002, Partial η2 = 0.070) and unspliced XBP1 (F(1/128)= 8.803, p= 0.004, Patial η2 = 0.065) were significantly decreased in BD. Spliced XBP1 (F(1/126) = 5.848, p = 0.017, Partial η2 = 0.044) and the ratio spliced XBP1/ unspliced XBP1 did not differ between BD and controls (F(1/126) = 0.599, p = 0.441, Partial η2 = 0.005). Gene expression did not differ between euthymia, depression and mania. DISCUSSION BiP gene expression was significantly higher in BD compared to controls. Total and unspliced XBP1 were significantly lower in BD than in the control group. Thus, both genes may be considered as putative trait markers. Nevertheless, XBP1 splicing itself did not differ between both groups.