Reduction of arterial stiffness in depressive individuals responding to multimodal treatment.

BACKGROUND: Depressive individuals are at higher risk for cardiovascular diseases (CVD). Thus, cardiovascular parameters such as arterial stiffness, often measured by pulse wave velocity (PWV), should be monitored. Recent research indicated that depressive individuals exhibit higher PWV, but there is little data on the changeability of PWV through multimodal treatment. This study investigated PWV in moderately to severe depressive individuals before and after undergoing treatment in dependence on responding or not responding to treatment. METHODS: 47 participants (31 females, 16 males) underwent a PWV measurement and filled out a questionnaire surveying depressive symptom severity before and after a six-week psychiatric rehabilitation treatment including multimodal interventions. Subjects were divided in responders and non-responders, depending on their treatment success. RESULTS: A mixed ANCOVA analysis indicated no significant main effect of responder status, but a significant main effect of measurement time and a significant interaction between responder status and measurement time. Responders exhibited a significant decrease in PWV across time, while no significant change in PWV across time was found for non-responders. LIMITATIONS: Results are limited by the lack of a control group. The influence of medication duration or medication type was not considered in the analyses. Causality of the relationship between PWV and depression cannot be determined. CONCLUSION: These findings show that PWV can be positively modified in depressive individuals responding to treatment. This effect cannot solely be attributed to pharmacological interventions but rather the combination of multimodal interventions, thus highlighting the clinical relevance of multimodal treatment in depression and comorbid disorders.

A one-year view on the association of metabolic syndrome and cognitive function in bipolar disorder - Preliminary data.

BACKGROUND: Individuals with bipolar disorder have a high prevalence of metabolic syndrome and an increased risk for cognitive deficits. The aim of this longitudinal study was to investigate the trajectory of cognitive decline in dependence of metabolic syndrome over a one-year interval. METHODS: 52 well-diagnosed individuals with bipolar disorder, euthymic at baseline and follow-up (n = 17 with metabolic syndrome vs. n = 35 without metabolic syndrome) were investigated with a comprehensive neurocognitive test battery (Trail Making Test A/B, Digit Symbol Test, California Verbal Leaning Test, or the Verbal Learning and Memory Test respectively) twice within the interval of one year. RESULTS: Patients with bipolar disorder and additional metabolic syndrome performed significantly worse in the domain of psychomotor and processing speed/attention than patients without metabolic syndrome at test point one. No deteriorating effects of metabolic syndrome on the cognitive domain scores and overall cognitive performance were found at the one-year follow up. However, no cognitive decline could be reported in both groups. LIMITATIONS: Time interval, small sample size and selection of metabolic syndrome affected patients were the major limitations of this study. CONCLUSION: There was no association of metabolic syndrome on the one-year trajectory of cognitive function in bipolar disorder. Future studies should expand the observation period and investigate larger samples.

Gene expression analysis of MAOA and the clock gene ARNTL in individuals with bipolar disorder compared to healthy controls.

INTRODUCTION: Circadian rhythms are associated with bipolar disorder (BD). This cross-sectional study aimed at investigating ARNTL and MAOA gene expression differences (1) between individuals with BD and controls, (2) between affective episodes, and (3) the relationship between ARNTL and MAOA expression. METHODS: ARNTL and MAOA gene expression in peripheral mononuclear blood cells were analysed from fasting blood samples (BD n = 81, controls n = 54) with quantitative real-time PCR operating on TaqMan® assays (normalised to 18S RNA expression). ANCOVAs corrected for age, sex, body mass index, and medication was used to evaluate expression differences and correlation analyses for the relation between ARNTL and MAOA expression. RESULTS: ARNTL gene expression differed between affective episodes (F(2,78) = 3.198, p = 0.047, Partial Eta2= 0.083), but not between BD and controls (n.s.). ARNTL and MAOA expression correlated positively in BD (r = 0.704, p < 0.001) and in controls (r = 0.932, p < 0.001). MAOA expression differed neither between BD and controls nor between affective episodes (n.s.). DISCUSSION: Clock gene expression changes were observed in different affective states of BD. More precisely, ARNTL gene expression was significantly higher in euthymia than in depression. ARNTL and MAOA gene expression correlated significantly in BD and in controls, which emphasises the strong concatenation between circadian rhythms and neurotransmitter breakdown.

Sex differences in zonulin in affective disorders and associations with current mood symptoms.

INTRODUCTION: The bidirectional connection between the brain and the gut within psychiatric entities has gained increasing scientific attention over the last years. As a regulator of intestinal permeability, zonulin acts as a key player on the interface of this interplay. Like several psychiatric disorders, intestinal permeability was associated with inflammation in previous findings. METHODS: In this study we explored differences in zonulin serum levels in currently depressed (n = 55) versus currently euthymic (n = 37) individuals with an affective disorder. Further, we explored sex differences and possible influences on zonulin and affective symptoms like medication, age, body mass index, and smoking status. RESULTS: Serum zonulin was significantly higher in females than in men independent from affective status (z = -2.412, p = .016). More specifically, females in the euthymic subgroup had higher zonulin levels than euthymic men (z = -2.114, p = .035). There was no difference in zonulin serum levels in individuals taking or not taking a specific psychopharmacotherapy. We found no correlation between zonulin serum levels and depression severity. DISCUSSION: Increased serum zonulin levels as a proxy for increased intestinal permeability in women may indicate a state of elevated susceptibility for depression-inducing stimuli.

The association between anti-inflammatory effects of long-term lithium treatment and illness course in Bipolar Disorder.

INTRODUCTION: Altered levels of acute-phase proteins are often described in different conditions in BD. Nevertheless, data on the association between lithium treatment and inflammatory markers in the long-term course of BD are still missing. The aim of the study was to examine the long-term course of BD concerning long-term lithium treatment, chronic inflammatory processes and symptom progression. Furthermore, the association between duration of lithium treatment and levels of hsCRP was explored. METHODS: 267 individuals (males= 139, females= 128) with BD were included. Duration of lithium treatment as well as symptom progression, defined as the increase in severity of symptoms, number of episodes a year and duration of episodes within a period of 1.5 years in the past and hsCRP were evaluated. RESULTS: Male individuals with symptom progression over time had significantly lower duration of lithium treatment compared to individuals without symptoms progression (U= 47.4, p=.037). There were significantly higher levels of hsCRP in male individuals with symptom progression compared to males without symptom progression (U= 47.5, p=.027). Further, there was a significant negative correlation between the duration of lithium treatment and hsCRP levels in the whole sample (r= -.276, p<.05). CONCLUSION: Our results show that an altered inflammatory state may be associated with a more severe illness course in BD. Further, a longer duration of lithium treatment may be associated with lower symptom progression. The shown association between hsCRP-levels and lithium treatment duration suggests a potential anti-inflammatory effect of lithium as a mediator of its significant positive outcome effect in BD.

The relationship between "Eyes Reading" ability and verbal memory in bipolar disorder.

In psychiatric disorders, neurocognitive impairments are prevalent and have been associated with poor outcome. Deficits in Theory of Mind (ToM, "mentalising") have also been observed in bipolar disorder (BD); however, the literature shows inconsistent data. The aim of this study was to explore ToM performance in a well-characterized sample of euthymic individuals with BD and its relationship with neurocognitive function. One hundred sixteen euthymic patients with BD between 18 and 74 years (mean age = 42.4, SD = 13.8) and 79 healthy controls (mean age = 39.8, SD = 16.5) were investigated with an extensive neurocognitive test battery (Trail Making Test A/B, d2 Test of Attention, Stroop Color-Word Test, California Verbal Learning Test, Multiple Choice Vocabulary Test). Additionally, all participants were given the Reading the Mind in the Eyes Test (RMET) to measure affective ToM, the ability to make assumptions about other people´s feelings. Overall, "Eyes Reading" performance was not impaired in individuals with BD compared with controls. However, a significant relationship between RMET and verbal memory in BD was shown, particularly in males. Data showed worse RMET performance in patients with memory deficits compared to patients without memory deficits and controls. Due to cross-sectional data, no conclusions can be made with respect to cause and effect.

Epigenetics of the molecular clock and bacterial diversity in bipolar disorder.

Objectives The gut microbiome harbors substantially more genetic material than our body cells and has an impact on a huge variety of physiological mechanisms including the production of neurotransmitters and the interaction with brain functions through the gut-brain-axis. Products of microbiota can affect methylation according to preclinical studies. The current investigation aimed at analyzing the correlation between gut microbiome diversity and the methylation of the clock gene ARNTL in individuals with Bipolar Disorder (BD). Methods Genomic DNA was isolated from fasting blood of study participants with BD (n = 32). The methylation analysis of the ARNTL CG site cg05733463 was performed by bisulfite treatment of genomic DNA with the Epitect kit, PCR and pyrosequencing. Additionally, DNA was extracted from stool samples and subjected to 16S rRNA sequencing. QIIME was used to analyze microbiome data. Results Methylation status of the ARNTL CpG position cg05733463 correlated significantly with bacterial diversity (Simpson index: r= -0.389, p = 0.0238) and evenness (Simpson evenness index: r= -0.358, p = 0.044). Furthermore, bacterial diversity differed significantly between euthymia and depression (F(1,30) = 4.695, p = 0.039). Discussion The results of our pilot study show that bacterial diversity differs between euthymia and depression. Interestingly, gut microbiome diversity and evenness correlate negatively with methylation of ARNTL, which is known to regulate monoamine oxidase A transcription. We propose that alterations in overall diversity of the gut microbiome represent an internal environmental factor that has an epigenetic impact on the clock gene ARNTL which is thought to be involved in BD pathogenesis.

Changes in the tryptophan-kynurenine axis in association to therapeutic response in clinically depressed patients undergoing psychiatric rehabilitation.

INTRODUCTION: In recent decades a number of studies have shown an association between the Tryptophan (Trp)-Kynurenine (Kyn) axis and neuropsychiatric disorders. However, the role of the Trp-Kyn pathway on the affective status in a general psychiatric cohort requires clarification. This study aimed to measure peripheral changes in Trp, Kyn and the Kyn/Trp-ratio as well as in the inflammatory markers high sensitive C-reactive protein (hsCRP) and interleukine-6 (IL-6) in individuals undergoing a six-week course of intensive treatment program comparing subgroups of treatment responders and non-responders. METHODS: In this investigation 87 currently depressed individuals with a life-time history of depressive disorders were divided into treatment responders (n = 48) and non-responders (n = 39). The individuals were selected for an extreme group comparison out of 598 patients undergoing a 6-week psychiatric rehabilitation program in Austria. Responders were defined according to great changes in Becks Depression Inventory (BDI-II) between time of admission and discharge (BDI-II > 29 to BDI-II <14), while non-responders had no or minimal changes (BDI >20, max. 4 points change over time). Differences in the levels of Trp, Kyn, and the Kyn/Trp ratio as well as levels of hsCRP and IL-6, were compared between groups. Differences were analyzed at the time of admission as well as at discharge. RESULTS: A significant group x time interaction was found for Kyn [F(1.82) = 5.79; p = 0.018] and the Kyn/Trp ratio [F(1.85) = 4.01, p = 0.048]. Importantly, Kyn increased significantly in the non-responder group, while the Kyn/Trp ratio decreased significantly in the responder group over time. Furthermore, changes in Kyn as well as hsCRP levels correlated significantly with changes in the body mass index over time (Kyn: r=0.24, p = 0.030; hsCRP: r=0.25, p = 0.021). No significant interactions were found for Trp and hsCRP, although they increased significantly over time. DISCUSSION: Given the limitations of the study, we could show that the therapeutic response to a multimodal treatment in clinically depressed patients not receiving cytokine treatment is associated with changes in Kyn levels and the Kyn/Trp ratio as well as with hsCRP. However, it is too early to draw any causal conclusion. Future research should clarify relevant clinical and neurobiological parameters associated with changes in Kyn levels and Kyn/Trp ratio, especially in regard to clinical response.

The role of tryptophan metabolism and food craving in the relationship between obesity and bipolar disorder.

BACKGROUND & AIMS: Individuals with bipolar disorder (BD) have a significantly increased risk of obesity-related conditions. The imbalance between food intake and energy expenditure is assumed to be a major risk factor for obesity in BD. This study analyzed food craving in relation to anthropometric, metabolic, and neurobiological parameters in a well-characterized cohort of euthymic individuals with BD. METHODS: One-hundred-thirty-five patients completed the Food-Craving Inventory assessing four categories of food craving (fat, fast-food, sweets and carbohydrate craving). Additionally, clinical, metabolic and anthropometric parameters were assessed. RESULTS: Higher levels of fat craving were observed in males, versus females, with BD. High levels of carbohydrate craving positively correlated with kynurenine and the kynurenine-to-tryptophan ratio. Higher serum nitrite and neopterin levels were related to fat craving. Parameters of fat metabolism (triglycerides, high-density lipoprotein) were associated with fat and fast-food craving. Anthropometric measures of obesity (e.g. body mass index, waist-to-hip-ratio) were not related to food craving. CONCLUSIONS: Overweight/obese individuals with BD show an increased driving of tryptophan down the kynurenine pathways, as indicated by an increase in the serum kynurenine-to-tryptophan ratio. The driving of tryptophan down the kynurenine pathway is mediated by immune-inflammatory activity and stress. The correlation of increased kynurenine with food craving, especially carbohydrate craving, probably indicates a regulatory deficit in the maintenance of chronic inflammatory processes in obesity and BD. Food craving seems to be of clinical importance in the treatment of metabolic disturbances in BD, although not associated with anthropometric measures of obesity. Rather, food craving correlates with blood metabolic parameters and an increased activation of the kynurenine pathway, both of which are linked to higher affective symptomatology and the development of cardiovascular diseases.

Gender differences in the association between physical activity and cognitive function in individuals with bipolar disorder.

INTRODUCTION: Bipolar disorder (BD) is accompanied by a high number of comorbidities and associated with an overall increased mortality. Especially obesity, systemic inflammatory processes and cognitive deficits are highly prevalent and increase with the course of illness. Physical activity (PA) is associated with beneficial effects on somatic comorbidities such as obesity or cardiovascular disease in individuals without psychiatric disorder. Furthermore, PA might increase neurocognitive performance and reduce systemic inflammation. OBJECTIVE: The aim of the study was to investigate the association between PA and neurocognitive function in euthymic individuals suffering from BD. METHODS AND PARTICIPANTS: 120 individuals with BD, euthymic at test time, completed the self-reported International Physical Activity Questionnaire (IPAQ) assessing PA of the past seven days and were accordingly assigned to a specific activity category (low, moderate or vigorous). Furthermore, clinical parameters were gathered and cognitive tests analysing verbal-dependent intelligence, attention, executive functioning as well as memory were administered. RESULTS: Female individuals in the vigorous PA group performed significantly higher in most of the cognitive domains compared to females with moderate or low PA. In males, we only found a significant difference in one test for attention between moderate/vigorous and the low activity group. CONCLUSION: Differences between PA groups in cognitive performance in female individuals with BD were obvious in almost all cognitive domains. As cognitive deficits are strongly associated with a worse course of disease and outcome, PA might offer a concomitant therapy targeting not only somatic comorbidities such as obesity and cardiovascular disease, but also neurocognition.

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.

Patatin-like phospholipase 3 (rs738409) gene polymorphism is associated with increased liver enzymes in obese adolescents and metabolic syndrome in all ages.

BACKGROUND: Obesity is associated with non-alcoholic fatty liver disease (NAFLD), and the patatin-like phospholipase 3 (PNPLA3) rs738409 (Ile148Met, C>G) gene polymorphism is one of the most important genetic determinants of NAFLD. Carriers have been reported to better respond to lifestyle modification. AIM: To investigate the effect of rs738409 on overweight/obese adolescents and adults with and without metabolic syndrome (MetS). METHODS: Two hundred and eighty-eight overweight/obese and 209 normal weight participants of the STYJOBS/EDECTA cohort (NCT00482924) were analysed for PNPLA3 genotypes. RESULTS: Compared to overweight/obese without MetS, in overweight/obese study participants with MetS, the presence of the G allele (148Met) was significantly higher (CC: 5.0% vs. 9.2%, Spearman's correlation, 0.12; P = 0.038). Persons with CG (heterozygote for the risk allele) and with GG (homozygote for the risk allele) genotypes showed significantly higher ALT levels than those with CC genotypes. Even young individuals aged below 20 years had significantly increased ALT levels if they were homozygote with the G allele. CONCLUSIONS: The PNPLA3 rs738409 polymorphism is associated already in youths with increased ALT, and is more frequent in obese with MetS of all ages. Hence, overweight/obese rs738409 carriers should be identified early in life and treated with a rigorous life style intervention.

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.

Disturbed tryptophan metabolism in cardiovascular disease.

Atherosclerosis (AS), a major pathologic consequence of obesity, is the main etiological factor of cardiovascular disease (CVD), which is the most common cause of death in the western world. A systemic chronic low grade immune- mediated inflammation (scLGI) is substantially implicated in AS and its consequences. In particular, proinflammatory cytokines play a major role, with Th1-type cytokine interferon-γ (IFN-γ) being a key mediator. Among various other molecular and cellular effects, IFN-γ activates the enzyme indoleamine 2,3-dioxygenase (IDO) in monocyte-derived macrophages, dendritic, and other cells, which, in turn, decreases serum levels of the essential amino acid tryptophan (TRP). Thus, people with CVD often have increased serum kynurenine to tryptophan ratios (KYN/TRP), a result of an increased TRP breakdown. Importantly, increased KYN/TRP is associated with a higher likelihood of fatal cardiovascular events. A scLGI with increased production of the proinflammatory adipokine leptin, in combination with IFN-γ and interleukin-6 (IL-6), represents another central link between obesity, AS, and CVD. Leptin has also been shown to contribute to Th1-type immunity shifting, with abdominal fat being thus a direct contributor to KYN/TRP ratio. However, TRP is not only an important source for protein production but also for the generation of one of the most important neurotransmitters, 5-hydroxytryptamine (serotonin), by the tetrahydrobiopterin-dependent TRP 5-hydroxylase. In prolonged states of scLGI, availability of free serum TRP is strongly diminished, affecting serotonin synthesis, particularly in the brain. Additionally, accumulation of neurotoxic KYN metabolites such as quinolinic acid produced by microglia, can contribute to the development of depression via NMDA glutamatergic stimulation. Depression had been reported to be associated with CVD endpoints, but it most likely represents only a secondary loop connecting excess adipose tissue, scLGI and cardiovascular morbidity and mortality. Accelerated catabolism of TRP is further involved in the pathogenesis of the anemia of scLGI. The pro-inflammatory cytokine IFN-γ suppresses growth and differentiation of erythroid progenitor cells, and the depletion of TRP limits protein synthesis and thus hemoglobin production, and, through reduction in oxygen supply, may contribute to ischemic vascular disease. In this review we discuss the impact of TRP breakdown and the related complex mechanisms on the prognosis and individual course of CVD. Measurement of TRP, KYN concentrations, and calculation of the KYN/TRYP ratio will contribute to a better understanding of the interplay between inflammation, metabolic syndrome, mood disturbance, and anemia, all previously described as significant predictors of an unfavorable outcome in patients with CVD. The review leads to a novel framework for successful therapeutic modification of several cardinal pathophysiological processes leading to adverse cardiovascular outcome.

[Oxidative stress in bipolar affective disorder]. / Oxidativer Stress bei bipolar affektiver Störung. (corrected).

The results of mortality studies have indicated that medical conditions, such as cardiovascular disease, obesity and diabetes are the most important causes of mortality among patients with bipolar disorder. The reasons for the increased incidence and mortality are not fully understood. Oxidative stress and an inadequate antioxidative system might be one missing link and could also help to further elucidate the pathophysiological basis of bipolar disorder. This article provides a comprehensive review of oxidative stress in general and about the existing data for bipolar disorder. In addition information is given about possible therapeutic strategies to reduce oxidative stress and the use in bipolar disorder.

[Bipolar disorder and compliance]. / Bipolar affektive Störung und Compliance.

According to literature data the lack of compliance is a massive problem in up to 50 % of the patients with bipolar affective disorders and can lead to severe long-term complications in the further course of the diseases. In this case report we present various strategies that are intended to improve compliance.