The influence of chronic inflammation on the illnesscourse of bipolar disorder: A longitudinal study.

INTRODUCTION: C-reactive protein (CRP) is a systemic inflammatory marker, which indicates systemic inflammatory processes It is involved in different inflammatory processes of the body and is a reliable marker for the general inflammatory state of the body. High sensitive CRP seems to play a key role as a state and trait marker of bipolar disorder (BD). In the current study, we tried to determine the long-term effect of CRP levels on clinical symptoms and illness course of bipolar disorder. METHODS: For the current study, we examined 106 patients with BD for a period of four years. Participants underwent a clinical screening for depressive and manic episodes with the Hamilton Depression Scale (HAMD) and the Young Mania Rating Score (YMRS) and a serological diagnostic for inflammatory parameters every six months, thus leading to 8 measurement times in total. Patients with the presence of severe medical or neurological comorbidities such as active cancer, chronic obstructive lung disease, rheumatoid arthritis, systemic lupus erythematosus, Alzheimer's disease, Parkinson's disease, Huntington's disease or multiple sclerosis and acute infections were not included in the study. RESULTS: In our sample, 26% showed a mean hsCRP above 5 mg/dl. Those patients showed a significantly higher mean YMRS score than those with a mean hsCRP under 5 mg/dl during our observation period. Regarding HAMD there was no significant difference in hsCRP values. The existence of lithium treatment showed no significant influence on mean hsCRP levels between the start and endpoint. CONCLUSION: Individuals who were exposed to a higher level of inflammation over time suffered from more manic symptoms in this period. These findings underline the hypothesis that inflammatory processes have an accumulative influence on the illness course of BD, especially concerning manic symptoms and episodes.

Interleukin-6 Gene Expression Changes after a 4-Week Intake of a Multispecies Probiotic in Major Depressive Disorder-Preliminary Results of the PROVIT Study.

Major depressive disorder (MDD) is a prevalent disease, in which one third of sufferers do not respond to antidepressants. Probiotics have the potential to be well-tolerated and cost-efficient treatment options. However, the molecular pathways of their effects are not fully elucidated yet. Based on previous literature, we assume that probiotics can positively influence inflammatory mechanisms. We aimed at analyzing the effects of probiotics on gene expression of inflammation genes as part of the randomized, placebo-controlled, multispecies probiotics PROVIT study in Graz, Austria. Fasting blood of 61 inpatients with MDD was collected before and after four weeks of probiotic intake or placebo. We analyzed the effects on gene expression of tumor necrosis factor (TNF), nuclear factor kappa B subunit 1 (NFKB1) and interleukin-6 (IL-6). In IL-6 we found no significant main effects for group (F(1,44) = 1.33, p = ns) nor time (F(1,44) = 0.00, p = ns), but interaction was significant (F(1,44) = 5.67, p < 0.05). The intervention group showed decreasing IL-6 gene expression levels while the placebo group showed increasing gene expression levels of IL-6. Probiotics could be a useful additional treatment in MDD, due to their anti-inflammatory effects. Results of the current study are promising, but further studies are required to investigate the beneficial effects of probiotic interventions in depressed individuals.

The Relationship Between Food Craving, Appetite-Related Hormones and Clinical Parameters in Bipolar Disorder.

Obesity and weight gain in bipolar disorder (BD) have multifactorial underlying causes such as medication side effects, atypical depressive symptomatology, genetic variants, and disturbances in the neuro-endocrinal system. Therefore, we aim to explore the associations between food craving (FC), clinical parameters, psychotropic medication, and appetite-related hormones. In this cross-sectional investigation, 139 individuals with BD and 93 healthy controls (HC) completed the food craving inventory (FCI). In addition, blood samples (including leptin and acylated ghrelin) were analyzed and sociodemographic and anthropometric data were collected. Individuals with BD reported higher frequencies of total FC as well as craving for fat and fast food than HC. Additionally, we found a significant negative correlation between FC and ghrelin levels in BD. Smokers with BD reported significantly more craving for high fat foods than non-smokers. Age was significantly associated with FC independent of group. Individuals with BD taking olanzapine and quetiapine reported higher frequencies of craving for sweet food, while patients currently taking lithium reported less total FC compared to those without lithium therapy. Likewise, patients currently taking valproate reported less total FC and less craving for sweets than those not taking valproate. FC appears to be of clinical relevance in individuals with BD. Contrary to previous data, this does not seem to be a female phenomenon only and might encompass more than the specific craving for carbohydrates. Although due to the cross sectional design, causality cannot be determined, the association between depressive symptomatology and fast food craving warrants further research.

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.

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

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.

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.

Genome-wide association study of 40,000 individuals identifies two novel loci associated with bipolar disorder.

Bipolar disorder (BD) is a genetically complex mental illness characterized by severe oscillations of mood and behaviour. Genome-wide association studies (GWAS) have identified several risk loci that together account for a small portion of the heritability. To identify additional risk loci, we performed a two-stage meta-analysis of >9 million genetic variants in 9,784 bipolar disorder patients and 30,471 controls, the largest GWAS of BD to date. In this study, to increase power we used ∼2,000 lithium-treated cases with a long-term diagnosis of BD from the Consortium on Lithium Genetics, excess controls, and analytic methods optimized for markers on the X-chromosome. In addition to four known loci, results revealed genome-wide significant associations at two novel loci: an intergenic region on 9p21.3 (rs12553324, P = 5.87 × 10 - 9; odds ratio (OR) = 1.12) and markers within ERBB2 (rs2517959, P = 4.53 × 10 - 9; OR = 1.13). No significant X-chromosome associations were detected and X-linked markers explained very little BD heritability. The results add to a growing list of common autosomal variants involved in BD and illustrate the power of comparing well-characterized cases to an excess of controls in GWAS.

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

OBJECTIVES: 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. METHODS: The aim of this investigation was to measure and compare peripheral levels of serum MMP9 and sICAM in adults with euthymic BD and healthy controls (HC). Furthermore, we focussed on correlations with illness severity and metabolic parameters. RESULTS: MMP9 levels among the BD sample (n = 112) were significantly higher than among the HC (n = 80) (MMP9: F = 9.885, p = 0.002, η(2)  = 0.058) after controlling for confounding factors. Patients with BD in a later, progressive stage of disease showed significantly higher MMP9 as well as sICAM-1 levels compared to patients with BD in an earlier stage of disease (MMP9: F = 5.8, p = 0.018, η(2)  = 0.054; sICAM-1: F = 5.6, p = 0.020, η(2)  = 0.052). Correlation analyses of cognitive measures revealed a negative association between performance on the d2 Test of Attention and MMP9 (r = -0.287, p = 0.018) in the BD sample. Despite the sample being euthymic (i.e., according to conventional criteria) at the time of analysis, we found significant correlations between MMP9 as well as sICAM-1 and subthreshold depressive/hypomanic symptoms. CONCLUSIONS: A collection of disparate findings herein point to a role of MMP9 and cICAM-1 in the patho-progressive process of BD: the increased levels of serum MMP9 and sICAM-1, the correlation between higher levels of these parameters, progressive stage, and cognitive dysfunction in BD, and the positive correlation with subthreshold symptoms. As sICAM-1 and MMP9 are reliable biomarkers of inflammatory and early atherosclerotic disease, these markers may provide indications of the presence of occult cardiovascular disease in this highly at-risk population.

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.