Magyar Geofizika 1988

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

DATA FOR Increased breakdown of kynurenine towards its neurotoxic branch in bipolar disorder PLOS ONE

The study was conducted at the Medical University of Graz, Department of Psychiatry. All patients took part in the ongoing single centre BIPFAT study, that assesses demographic parameters, complete actual and lifetime psychiatric history using the Structured Clinical Interview according to DSM-IV (SCID I),, history of medication, anthropometric measure, blood pressure, fasting blood, cognitive testing, EEG, stool sample, different lifestyle questionnaires and magnetic resonance imaging (MRI) of the brain. All patients included were former in- or outpatients of the Medical University of Graz and had a diagnosis of BD I or BD II according to the DSM-IV criteria. Patients needed to be in the state of euthymia or mild depression (HAM-D score <14 and YMRS <9) and had given written informed consent prior to participating in the study. The study has been approved by the local ethics committee (Medical University of Graz, Austria) in compliance with the current revision of the Declaration of Helsinki, ICH guideline for Good Clinical Practice and current regulations (EK-number: 24-123 ex 11/12). Exclusion criteria were the presence of chronic obstructive pulmonary disease, rheumatoid arthritis, systemic lupus erythematosus, inflammatory bowel disease, neurodegenerative and neuroinflammatory disorders (i.e. Alzheimer's, Huntington's and Parkinson's disorder, multiple sclerosis), hemodialysis and interferon-α-based immunotherapy. Further exclusion criteria for controls were the presence of lifetime psychiatric diagnoses (verified by SCID I) and first and second grade relationship to relatives with psychiatric disorders. We took peripheral TRYCAT blood levels of 143 euthymic and mild depressive BD patients and 101 healthy controls. Targeted parameters were the levels of KYN, KYNA, 3-HK and AA, the ratio 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. Because of technical issues AA could only be evaluated in 113 BD and 88 HC. The analyzation took place at the Institute of Laboratory Medicine, Medical Center of Ludwig Maximilian University, Munich, Germany

Serum levels of TRYCATs in ng/mL.

<p>Results from MANCOVA controlled for age, sex, body mass index, presence of a cardiovascular disease and smoking; *p<0.05; KYN = kynurenine, KYNA = kynurenic acid, 3-HK = 3-hydroxykynurenine, AA = anthranilic acid.</p

Scatter graphs showing the distributions of the TRYCAT metabolism ratios.

<p>Scatter graphs showing the distributions of the TRYCAT metabolism ratios.</p

Scatter graphs showing the distribution of the serum levels of the measured TRYCATs in ng/mL.

<p>Scatter graphs showing the distribution of the serum levels of the measured TRYCATs in ng/mL.</p

Ratios of TRYCAT metabolism.

<p>Results from MANCOVA controlled for age, sex, body mass index, presence of a cardiovascular disease and smoking; *p<0.05, **p<0.01; KYN = kynurenine, KYNA = kynurenic acid, 3-HK = 3-hydroxykynurenine, AA = anthranilic acid.</p

Demographic and clinical parameters.

<p>Demographic and clinical parameters.</p