Regulation of Zbp1 by miR-99b-5p in microglia controls the development of schizophrenia-like symptoms in mice.

Current approaches to the treatment of schizophrenia have mainly focused on the protein-coding part of the genome; in this context, the roles of microRNAs have received less attention. In the present study, we analyze the microRNAome in the blood and postmortem brains of schizophrenia patients, showing that the expression of miR-99b-5p is downregulated in both the prefrontal cortex and blood of patients. Lowering the amount of miR-99b-5p in mice leads to both schizophrenia-like phenotypes and inflammatory processes that are linked to synaptic pruning in microglia. The microglial miR-99b-5p-supressed inflammatory response requires Z-DNA binding protein 1 (Zbp1), which we identify as a novel miR-99b-5p target. Antisense oligonucleotides against Zbp1 ameliorate the pathological effects of miR-99b-5p inhibition. Our findings indicate that a novel miR-99b-5p-Zbp1 pathway in microglia might contribute to the pathogenesis of schizophrenia.

Machine-based learning of multidimensional data in bipolar disorder - pilot results.

INTRODUCTION: Owing to the heterogenic picture of bipolar disorder, it takes approximately 8.8 years to reach a correct diagnosis. Early recognition and early intervention might not only increase quality of life, but also increase life expectancy as a whole in individuals with bipolar disorder. Therefore, we hypothesize that implementing machine learning techniques can be used to support the diagnostic process of bipolar disorder and minimize misdiagnosis rates. MATERIALS AND METHODS: To test this hypothesis, a de-identified data set of only demographic information and the results of cognitive tests of 196 patients with bipolar disorder and 145 healthy controls was used to train and compare five different machine learning algorithms. RESULTS: The best performing algorithm was logistic regression, with a macro-average F1-score of 0.69 [95% CI 0.66-0.73]. After further optimization, a model with an improved macro-average F1-score of 0.75, a micro-average F1-score of 0.77, and an AUROC of 0.84 was built. Furthermore, the individual amount of contribution per variable on the classification was assessed, which revealed that body mass index, results of the Stroop test, and the d2-R test alone allow for a classification of bipolar disorder with equal performance. CONCLUSION: Using these data for clinical application results in an acceptable performance, but has not yet reached a state where it can sufficiently augment a diagnosis made by an experienced clinician. Therefore, further research should focus on identifying variables with the highest amount of contribution to a model's classification.

Endoscopic trans-sphenoidal pituitary surgery does not impact postoperative nasal quality of life.

PURPOSE: The aim of this prospective longitudinal study was to assess both subjective quality of life using questionnaires and objective examination of nasal function with regard to olfaction, nasal air flow and mucociliary clearance in patients after minimally invasive, turbinate-preserving endoscopic transnasal trans-sphenoidal pituitary surgery. METHODS: Patients undergoing endoscopic transnasal pituitary surgery were recruited prospectively and examined during three study visits, preoperatively and 3 and 6 months postoperatively. We examined nasal function using sniffin' sticks test, rhinomanometry, saccharin transit time test, and endoscopic and radiological scores. In addition, the influence on subjective quality of life and mental health was recorded using the Sinonasal-Outcome-Test-20 (SNOT-20) and the Hospital-Anxiety-and-Depression-Scale (HADS). RESULTS: 20 patients undergoing endoscopic pituitary tumor resections were included. No significant changes in olfaction or mucociliary clearance were noted. Nasal air flow showed a tendency to increase in the postoperative course lacking significance. Both the endoscopy and the radiological scores showed a significant deterioration, especially after 3 months, with a trend towards improvement over time. However, neither the SNOT-20 nor the HADS showed significant changes compared to baseline. CONCLUSIONS: Our concept of minimally invasive endoscopic tumor resections on the pituitary gland with preservation of nasal turbinates shows low morbidity for the patient. Despite objectifiable surgery-associated changes in the nose, nasal physiology in terms of smell, airflow and mucociliary clearance can be preserved and the subjective quality of life of our patients remains stable.

Delirium-associated medication in people at risk: A systematic update review, meta-analyses, and GRADE-profiles.

BACKGROUND: Drug-associated delirium is a common but potentially preventable neuropsychiatric syndrome associated with detrimental outcomes. Empirical evidence for delirium-associated medication is uncertain due to a lack of high-quality studies. We aimed to further investigate the body of evidence for drugs suspected to trigger delirium. METHODS: A systematic update review and meta-analyses of prospective studies presenting drug associations with incident delirium in adult study populations was conducted. Two authors independently searched MEDLINE, PsycINFO, Embase, and Google Scholar dated from October 1, 2009 to June 23, 2020, after screening a previous review published in 2011. The most reliable results on drug-delirium associations were pooled in meta-analyses using the random-effects model. Quality of evidence was assessed using the GRADE-approach. This study is preregistered with OSF (DOI https://doi.org.10.17605/OSF.IO/4PUHY). RESULTS: The 31 eligible studies, presenting results for 24 medication classes were identified. Meta-analyses and GRADE level of evidence ratings show no increased delirium risk for Haloperidol (OR: 0.96, 95% CI 0.72-1.28; high-quality evidence), Olanzapine (OR: 0.25, 95% CI 0.15-0.40), Ketamine (OR: 0.72, 95% CI 0.35-1.46) or corticosteroids (OR: 0.69, 95% CI 0.32-1.50; moderate quality evidence, respectively). Low-level evidence suggests a three-fold increased risk for anticholinergics (OR: 3.11, 95% CI 1.04-9.26). Opioids, benzodiazepines, H1 -antihistamines, and antidepressants did not reach reliable evidence levels in our analyses. CONCLUSION: We investigated the retrievable body of evidence for delirium-associated medication. The results of this systematic review were then interpreted in conjunction with other evidence-based works and guidelines providing conclusions for clinical decision-making.

The Association of Tube Weaning and Oral Skill Development in Infants With Tube Dependency: A Prospective Study.

OBJECTIVE: This study was the first of its kind by assessing oral skills development during and after applying the "Graz Model" of tube weaning. METHODS: This prospective case series study included data of 67 (35 females, 32 males, treated from March 2018 to April 2019) tube dependent children, who participated in the effective "Graz Model" of tube weaning. Parents filled out the standardized Pediatric Assessment Scale for Severe Feeding Problems (PASSFP) prior to and immediately after completion of the program. Paired sample t tests were conducted to examine pre-to-post changes in the children's oral skills. RESULTS: The study showed that oral skills increased significantly during tube weaning PASSFP score of 24.76 (standard deviation, SD = 12.38) prior to versus 47.97 (SD = 6.98) after completion of the program. Furthermore, significant changes in their sensory and tactile perception and in their general eating behavior were observed. Children also showed reduced oral aversion symptoms and food pocketing, could enjoy their meals, and increased their food repertoire. Mealtime duration could be decreased, and parents were less anxious about their infants' intake and less frustrated because of their children's eating behavior. CONCLUSION: The results of this study demonstrated for the first time that tube dependent children can improve their oral skills significantly during and after their participation in the child-led approach of the "Graz model" of tube weaning.

Eating Habits and Eating Disorder Associated Behavior in Bipolar Disorder.

ABSTRACT: A relevant comorbidity of bipolar disorder (BD) is eating disorders (EDs). Crossed vulnerability factors as eating disorder-specific symptoms (EDSSs) may trigger the onset of both disorders in either direction. The Structured Inventory for Anorexic and Bulimic Eating Disorders for Self-Report was used to examine the occurrence of EDs in euthymic/subsyndromal individuals with BD ( n = 86) and healthy controls ( n = 86) matched for age and sex. Furthermore, we explored EDSSs with the subscales "general psychopathology and social integration," "bulimic symptoms," "body image and slimness ideal," "sexuality and body weight," "counteract," and "atypical binge." Higher rates of all EDSSs were reported in BD. Younger individuals with BD showed higher expression in "bulimic symptoms," "body image and slimness ideal," and "atypical binge" subscales. No participants fulfilled ED diagnosis. The findings show a link between EDSS and BD. Clinicians should pay attention to a multimodal intervention, considering risk factors, investigating eating habits and ED associated behaviors.

Sex-Related Differences in the Pharmacological Treatment of Major Depression - Are Women and Men Treated Differently?

BACKGROUND: In the last decade, sex-related medicine has become an increasingly important area of research as insights in this field can improve treatment strategies and recovery. The aim of this study was to investigate sex-related differences in the prescription and kinds of psychopharmacological treatment in individuals with unipolar affective disorder. SUBJECTS AND METHODS: Data collected on 388 patients attending a psychiatric rehabilitation clinic (194 females, 194 males, mean age 52.3 years, standard deviation 7.8 years), who were matched by age and severity of depression, were analyzed. Depression severity and information on drug type and quantity were assessed at the beginning of the rehabilitation program and compared between women and men. RESULTS: A significant difference between females and males was found in the frequency of prescribing bupropion (females: 3.61%, males: 12.89%; p=0.001) and mirtazapine (females: 5.15%, males: 13.40%; p=0.005). In terms of polypharmacy, the results showed that over 53% of the patients were taking two or more psychotropic substances as a long-term therapy and that 34% of them were taking three to five different substances. No sex-related differences were found concerning the number of psychotropic drugs taken by the patients. CONCLUSION: The higher frequency of prescriptions for bupropion and mirtazapine in men might be explained by the adverse drug reactions of the drugs (e.g., fewer sexually adverse drug reactions, weight gain) and a known interaction with oral contraception. It remains unclear whether these aspects are taken into consideration for each patient in terms of their special needs and conditions or whether it is a decision based on the patient's sex. Given a similar severity of depression, men and women are prescribed a similar number of psychotropic substances. However, the high number of psychotropic drugs prescribed on average should be noted. Well-trained healthcare professionals should focus on regularly assessing and optimizing treatment regimens.

The Outcome of Psychiatric Rehabilitation Treatment Depends on Affective State at the Time of Admission.

BACKGROUND: In Austria, new approaches of rehabilitation programs focus on the prevention of mental illness and offer treatment not only for acute psychiatric patients, but also for those who are at risk of developing a mental disorder or have recovered from one.The aim of this study was to determine the effects of a psychiatric rehabilitation program on individuals with different mood states. SUBJECTS AND METHODS: 600 patients with a history of affective disorder were tested at the time of admission to an Austrian inpatient psychiatric rehabilitation center. Data of extreme groups - patients who were depressed (n=59; BDI-II<9 and HAMD<8) or euthymic (n=59; BDI<18 and HAMD>19) at the time of therapy start - were analyzed. The participants completed the Maslach Burnout Inventory - General Survey, the Symptom Checklist - Revised and the Stress Coping Questionnaire at the beginning and the end of the 6-weeks rehabilitation program. RESULTS: After 6 weeks, both groups showed significantly less psychiatric symptoms (BDI-II, HAMD, SCL-90, and negative coping strategies (SVF). Importantly, work-related stress symptoms ("burnout" symptoms) improved significantly in the euthymic group. CONCLUSIONS: Euthymic patients seem to be able to focus on work-related stress symptoms including reduced emotional exhaustion through treatment, while currently depressed patients primarily benefit by an improvement in general psychiatric symptomatology. The results indicate the crucial role of mood state validated with standardized psychological questionnaires BDI-II and HAMD at time of admission to such programs. These findings could have implications on treatment decisions for psychiatric patients and assist in making a forecast concerning ability to recover and treatment prognosis.

Body Mass Index Predicts Decline in Executive Function in Bipolar Disorder: Preliminary Data of a 12-Month Follow-up Study.

INTRODUCTION: Obesity and associated risk factors have been linked to cognitive decline before. OBJECTIVES: In the present study, we evaluated potential cumulative negative effects of overweight and obesity on cognitive performance in euthymic patients with bipolar disorder (BD) in a longitudinal design. METHODS: Neurocognitive measures (California Verbal Learning Test, Trail Making Test [TMT] A/B, Digit-Symbol-Test, Digit-Span, d2 Test), anthropometrics (e.g., body mass index [BMI]), and clinical ratings (Hamilton Depression Scale, Young Mania Rating Scale) were collected over a 12-month observation period. Follow-up data of 38 patients with BD (mean age 40 years; 15 males, 23 females) were available. RESULTS: High baseline BMI predicted a decrease in the patient's performance in the Digit-Span backwards task measuring working memory performance. In contrast, cognitive performance was not predicted by increases in BMI at follow-up. Normal weight bipolar patients (n = 19) improved their performance on the TMT B, measuring cognitive flexibility and executive functioning, within 1 year, while overweight bipolar patients (n = 19) showed no change in this task. CONCLUSIONS: The results suggest that overweight can predict cognitive performance changes over 12 months.

Probiotic Treatment in Individuals with Euthymic Bipolar Disorder: A Pilot-Study on Clinical Changes and Compliance.

The importance of the microbiome for psychological well-being has gained rising interest in the last decade. A strategy to examine the role of the microbiome in different diseases is the intake of supplements that modulate the gut microbiome. Despite promising results in animal studies, research in humans is sparse to date and especially in individuals with psychiatric disorders almost missing. The current report of the ProbioBIP-one pilot study aims at describing general effects of the intake of the probiotic OMNi-BiOTiC Stress repair® on psychological parameters as well as gastrointestinal symptoms and general compliance in a cohort of euthymic individuals with bipolar disorder (BD), receiving daily probiotic treatment over a time period of 3 months. Twenty-seven individuals with BD took part in the present study (mean age = 50.7 years, SD = 12.2; females 40.7%). In sum, there was a high compliance rate with 81.5% of the study participants completing all 3 study visits and 85% of planned probiotic ingestions taken. Gastrointestinal problems were prevalent in more than half of the patients at the time of inclusion (t1). Expectedly, in the whole cohort, a high proportion of study participants experienced changes concerning digestion during probiotic treatment, around one third reported positive changes (reduced flatulence and easier and more frequent bowel movements) after 1 month (t2) and further after 3 months (t3). In contrast, a smaller part of study participants reported gastrointestinal discomfort after 1 and after 3 months (mainly flatulence and obstipation). We found a significantly reduced cognitive reactivity to sad mood between t2 and t3 indicating that participants under probiotic supplementation perceived themselves to be less distracted by ruminative thoughts. Further changes in psychiatric symptoms were small due to the euthymic state and already low scoring at the time of inclusion. Nevertheless, we found a significant symptom reduction in the rating scales measuring manic symptoms. From a clinical point of view, probiotic supplementation might provide a well-tolerated tool to positively influence gastrointestinal quality of life as well as mental and somatic health, cognition and immune response and potentially have effects on psychiatric symptoms.

Efficacy of a standardized tube weaning program in pediatric patients with feeding difficulties after successful repair of their esophageal atresia/tracheoesophageal fistula.

Children born with esophageal atresia (EA) might suffer from significant oral feeding problems which could evolve into tube dependency. The primary aim of the study was to define the outcome of tube weaning in children after successful EA repair and to compare outcomes in children with short gap/TEF (tracheoesophageal fistula) and long-gap EA. Data of 64 children (28 with short-gap EA/TEF with primary anastomosis and 36 with long-gap EA with delayed surgical repair) who participated in a standardized tube weaning program based on the "Graz model of tube weaning" (in/outpatients in an intensive 3-week program, online coaching (Netcoaching) only, or a combined 2-week intensive onsite followed by online treatment "Eating School") from 2009 to 2019 was evaluated. Sixty-one patients completed the program by transitioning to exclusive oral intake (95.3%). Three children (4.7%) were left partially weaned at the time of discharge. No significant differences could be found between short gap/TEF and long-gap EA group regarding outcomes.Conclusions: The study's findings support the efficacy of tube weaning based on the published "Graz model of tube weaning" for children born with EA/TEF and indicate the necessity of specialized tube weaning programs for these patients. What is Known: • Children with esophageal atresia/tracheoesophageal fistula often suffer from feeding problems and tube dependency. • Different tube weaning programs and outcomes have been published, but not specifically for children with EA. What is New: • Evaluation of a large sample of children referred for tube weaning after EA repair. • Most children with EA can be weaned off their feeding tubes successfully after attending a specialized tube weaning program.

A step ahead: Exploring the gut microbiota in inpatients with bipolar disorder during a depressive episode.

OBJECTIVES: There is evidence that the gut microbiota plays a major role in the pathogenesis of diseases of the central nervous system through the gut-brain axis. The aim of the present study was to analyze gut microbiota composition in bipolar disorder (BD) and its relation to inflammation, serum lipids, oxidative stress, tryptophan (TRP)/kynurenine (KYN) levels, anthropometric measurements and parameters of metabolic syndrome. Further, microbial community differences of individuals with BD compared with healthy controls (HC) were explored. METHODS: In this cross-sectional study, we performed 16S rRNA gene sequencing of stool samples from 32 BD individuals and 10 HC. Laboratory parameters included inflammatory markers, serum lipids, KYN, oxidative stress and anthropometric measures. Microbial community analysis and correlation to clinical parameters was performed with QIIME, differential abundance analysis of taxa encompassed linear discriminant analysis effect size (LEfSe). RESULTS: We found a negative correlation between microbial alpha-diversity and illness duration in BD (R = -0.408, P = 0.021). Furthermore, we identified bacterial clades associated with inflammatory status, serum lipids, TRP, depressive symptoms, oxidative stress, anthropometrics and metabolic syndrome in individuals with BD. LEfSe identified the phylum Actinobacteria (LDA= 4.82, P = 0.007) and the class Coriobacteria (LDA= 4.75, P = 0.010) as significantly more abundant in BD when compared with HC, and Ruminococcaceae (LDA= 4.59, P = 0.018) and Faecalibacterium (LDA= 4.09, P = 0.039) as more abundant in HC when compared with BD. CONCLUSIONS: The present findings suggest that causes and/or consequences of BD may also lie outside the brain. Exploratory research of the gut microbiota in affective disorders like BD may identify previously unknown underlying causes, and offer new research and therapeutic approaches to mood disorders.

The Impact of Probiotic Supplements on Cognitive Parameters in Euthymic Individuals with Bipolar Disorder: A Pilot Study.

INTRODUCTION: Cognitive dysfunction is prevalent in depressive as well as manic episodes in individuals with Bipolar Disorder (BD). Even more, after symptom remission, many individuals with BD experience persisting cognitive impairment also in euthymic periods, leading to high illness burden and low quality of life. According to a recent research in animals and healthy humans, microbiota may influence cognitive processes via the brain-gut axis. A strategy to examine the role of the microbiota in different diseases is the intake of supplements that modulate the gut microbiome. The aim of this pilot study was to analyze the impact of probiotic supplements on cognitive parameters in a cohort of euthymic individuals with BD, receiving daily probiotic treatment over a time period of 3 months. METHODS: A total of 20 euthymic individuals with BD received probiotic supplement over a time period of 3 months and completed a cognitive test battery at 3 time points (t1 at time of inclusion, t2 after one month and t3 after 3 months of probiotic intake). RESULTS: We found a significant improvement of performance concerning attention and psychomotor processing speed measured with the Digit Symbol Test after one (t2) as well as after 3 months (t3) of treatment (F = 8.60; η2 = 0.49, p < 0.01). Furthermore, executive function measured with the TMT-B, increased significantly over 3 months (F = 3.68; η2 = 0.29, p < 0.05). CONCLUSION: The results confirm the hypotheses that probiotic supplement might help stable individuals with BD to improve the cognitive function, which in turn might lead to better psychosocial, occupational, work and financial functioning. Nevertheless, the idea of this potential new treatment is challenging because of the variety of the human's gut microbiota.

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.

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

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.

Brain electrical source imaging in manic and depressive episodes of bipolar disorder.

OBJECTIVE: Bipolar disorder (BD) electroencephalographic (EEG) studies have reported varying results. The present study compared EEG in BD during manic and depressive episodes, using brain electrical source imaging [standardized low-resolution electromagnetic tomography (sLORETA)] to assess the cortical spatial distribution of the sources of EEG oscillation frequencies. METHODS: Two independent datasets (a total of 95 patients with bipolar I disorder, of whom 59 were female) were analyzed. Dataset #1 comprised 14 patients in a manic as well as a depressive episode. Dataset #2 comprised 26 patients in a manic episode and 55 patients in a depressive episode. From the head surface-recorded EEG, sLORETA cortical activity was computed in eight EEG frequency bands, and compared between mood states in both datasets. The results from the two datasets were combined using conjunction analysis. RESULTS: Conjunction analysis yielded significant differences between mood states: In manic compared to depressive states, patients had lesser theta frequency band activity (right-hemispheric lateral lower prefrontal and anterior temporal, mainly Brodmann areas 13, 38, and 47), and greater beta-2 and beta-3 frequency band activity (extended bilateral prefrontal-to-parietal, mainly Brodmann area 6, and the cingulate). CONCLUSIONS: The spatial organization of the brain's electrical oscillations differed in patients with BD between manic and depressive mood states. The brain areas implementing the main functions that show opposing abnormalities during manic and depressive episodes were affected by unduly increased or decreased activity (beta or theta). The discussion considers that facilitating (beta) or inhibiting (theta) electrical activity can in either case result in behavioral facilitation or inhibition, depending on the function of the brain area.

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

OBJECTIVES: 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. METHODS: We investigated the tryptophan-kynurenine metabolism pathway as a proxy of dysregulated inflammatory homeostasis in euthymic, overweight individuals with BD (n = 78) compared to healthy controls (n = 156). RESULTS: Both blood kynurenine concentrations and the kynurenine to tryptophan ratio [(Kyn:Trp); an estimate of tryptophan breakdown] were significantly higher in the total sample of euthymic patients with BD, with greater increases noted in both parameters in the subsample of overweight patients with BD. When compared to controls, peripheral neopterin concentrations were significantly lower. Within the BD group, there were also significant between-group differences in neopterin concentrations, with higher levels in those who were overweight and in subjects with BD in the later stages of illness compared to earlier stages. CONCLUSIONS: Increased tryptophan breakdown, as well as neopterin levels in BD, may be an indirect mediator of immune-mediated inflammation. In BD, this may account for the high prevalence of medical comorbidities and increased mortality. The observation of increased kynurenine levels and Kyn:Trp, and altered circulating neopterin levels provides indirect evidence of increased activity of tryptophan-degrading indoleamine 2,3-dioxygenase in euthymic individuals with BD, underscoring the role of inflammatory mediators as a causative and/or consequent factor. More robust abnormalities in the overweight subsample underscore the additional inflammatory burden of medical comorbidity and suggest a shared pathophysiology as well as a mechanism mediating BD and cardiovascular disease.

Changes in tryptophan breakdown associated with response to multimodal treatment in depression.

Background: Research on depression showed that dysregulations in tryptophan (TRP), kynurenine (KYN), and its KYN pathway metabolites are key aspects in the development and maintenance of depressive symptoms. In our previous reports, we described sex-specific changes in TRP breakdown as well as changes in KYN and KYN/TRP in association with treatment response and inflammatory and metabolic parameters. However, results of treatment effects on KYN pathway metabolites as well as how pathway changes are related to treatment response remain sparse. Objective: We investigated potential changes of KYN and KYN pathway metabolites in association with therapeutic response of individuals with depression during a six-week multimodal psychiatric rehabilitation program. Methods: 87 participants were divided into treatment responders and non-responders (48 responders, 39 non-responders; 38 male, 49 female; M age = 51.09; SD age = 7.70) using scores of psychological questionnaires. KYN pathway metabolites serum concentrations as well as their ratios were collected using high performance liquid chromatography. Changes over time (time of admission (t1) vs. time of discharge (t2)) were calculated using repeated measure analyses of (co)variance. Results: Non-responders exhibited higher levels of 3-Hydroxyanthralinic acid (3-HAA), nicotinic acid (NA), and 3-HAA/KYN, independently of measurement time. NA levels decreased, while 3-HAA levels increased over time in both groups, independently of treatment response. 3-HK/KYN levels decreased, while KYN levels increased in non-responders, but not in responders over time. Discussion: The results indicate that some compounds of the KYN pathway metabolites can be altered through multimodal long-term interventions in association with treatment response. Especially the pathway degrading KYN further down to 3-HAA and 3-HK/KYN might be decisive for treatment response in depression.

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.

Theory of mind abilities during the course of bipolar disorder: A longitudinal study using mixed models.

Theory of mind (ToM) deficits, difficulties in recognizing the intentions, propensities, and beliefs of others have been shown in individuals with bipolar disorder in several studies; however, it is not yet elucidated how ToM abilities changes over the course of bipolar disorder and is related to illness symptoms. This is one of the first longitudinal studies to compare the ToM abilities of euthymic bipolar individuals and healthy controls over a four and a half years period. ToM abilities were measured using the Reading the Mind in the Eyes Test (RMET). A total of 91 euthymic bipolar individuals and 91 healthy controls were included in the analyses. Linear mixed models were used to compare ToM abilities of bipolar individuals and healthy controls. It was found that bipolar individuals scored lower on average on the RMET than healthy controls and that these RMET scores were stable over four and a half years. The results of this study suggest that ToM deficits are a stable (possibly endophenotypic) trait of bipolar disorder. This understanding can contribute to better identification, assessment, and treatment strategies for individuals with bipolar disorder, ultimately improving their overall care and outcome.