Pathogenetic Mechanisms of Mental Disorders: Endogenous Intoxication.

The review describes the syndrome of endogenous intoxication in patients with mental disorders. Oxidative stress, middle-mass endotoxic molecules, impaired functional properties of serum albumin and albumin thiol groups, neurotrophic factors, and enzymes, including monoamine oxidase and semicarbazide-sensitive amine oxidase contribute to the development of endogenous intoxication. Possible pathogenetic mechanisms of the endogenous intoxication development in mental disorders and approaches to its treatment are discussed.

Monoamine Oxidase as a Potential Biomarker of the Efficacy of Treatment of Mental Disorders.

The review summarizes the results of our own studies and published data on the biological markers of psychiatric disorders, with special emphasis on the activity of platelet monoamine oxidase. Pharmacotherapy studies in patients with the mixed anxiety-depressive disorder and first episode of schizophrenia have shown that the activity of platelet monoamine oxidase could serve as a potential biomarker of the efficacy of therapeutic interventions in these diseases.

Influence of Antipsychotic Drug Risperidone on Human Serum Albumin Affinity to Organic Anions.

BACKGROUND: Risperidone is an antipsychotic drug. In blood, this drug binds mainly to human serum albumin (HSA) and is also transported by HSA. METHOD: To study certain details of the interaction between risperidone and HSA, a fluorescent dye CAPIDAN was used as a reporter. This dye specifically fluoresces from HSA in serum and is highly sensitive to structural changes in HSA including pathology-induced changes. Interaction of CAPIDAN with HSA has been studied using time-resolved fluorescence techniques. RESULT: The addition of phenylbutazone, a marker for the HSA drug-binding site I, leads to displacement of CAPIDAN from this site due to direct competition between phenylbutazone and the dye. The addition of risperidone induces a response of CAPIDAN fluorescence that is highly similar to its response to phenylbutazone. This response depends strongly on ionic strength and is very similar in both cases, phenylbutazone and risperidone. This similarity suggests that risperidone binds to HSA in the region of site I. In this site, the risperidone molecule probably covers the positive charge of Arginine 218 or Arginine 222 preventing their interaction with the CAPIDAN negatively charged carboxyl group. This effect was observed both in isolated HSA and in serum, suggesting similarity of the interaction. CONCLUSION: Thus, risperidone is able to prevent binding of organic anions (i.e. CAPIDAN as a drug-like molecule) to HSA.

A fluorescent reporter detects details of aromatic ligand interference in drug-binding sites of human serum albumin.

Human serum albumin (HSA) transports many ligands including small aromatic molecules: metabolites, drugs etc. Phenylbutazone is an anti-inflammatory drug, which binds to the drug-binding site I of HSA. Its interaction with this site has been studied using a fluorescent dye, CAPIDAN, whose fluorescence in serum originates from HSA and is sensitive to the changes in HSA site I in some diseases. Its fluorescence in HSA solutions is strongly suppressed by phenylbutazone. This phenomenon seems to be a basic sign of a simple drug-dye competition. However, a more detailed study of the time-resolved fluorescence decay of CAPIDAN has shown that phenylbutazone lowers fluorescence without changing the total amount of bound dye. In brief, the HSA-bound dye forms three populations due to three types of environment at the binding sites. The first two populations probably have a rather strong Coulomb interaction with the positive charge of residues Arginine 218 or Arginine 222 in site I and are responsible for approximately 90% of the total fluorescence. Phenylbutazone blocks this interaction and therefore lowers this fluorescence. At the same time the binding of the third population increases considerably in the presence of phenylbutazone, and, as a result, the actual number of bound dye molecules remains almost unchanged despite the ligand competition. So, time resolved fluorescence of the reporter allows to observe details of interactions and interference of aromatic ligands in drug binding site I of HSA both in isolated HSA and in serum.

Aspects of metabolic changes in first-episode drug-naïve schizophrenic patients.

UNLABELLED: Aim The aim of the study was to investigate the state of parameters characterising different sites of metabolism and the degree of endogenous intoxication in first-episode drug-naïve schizophrenic [first episode of schizophrenia (FES)] patients. It is hypothesised that the FES is the initial step in the development of pathologically disturbed biochemical status that is characteristic of chronic schizophrenia. METHODS: Platelet monoamine oxidase (MAO) and serum semicarbazide-sensitive amine oxidase (SSAO) activities, serum concentrations of middle-mass endotoxic molecules (MMEM) and malondialdehyde and parameters of the serum albumin functional state were measured in 26 FES patients and 15 age-matched healthy controls. RESULTS: Severity of disorder before the treatment was 75.5 ± 2.2, according to Positive and Negative Syndrome Scale score. FES patients were characterised by significant increase in MAO activity (99%) and MMEM concentration (124%) and significant decrease in SSAO activity (26%) as compared with controls. Changes of all other parameters were insignificant. Regression analysis has showed a significant relationship of three parameters - MAO, SSAO and MMEM, with values of PANNS score. Two methods of extraction of factor analysis revealed that MAO and SSAO belonged to Factor 1, whereas MMEM and albumin functional parameters belonged to Factor 2. CONCLUSION: Comparing our earlier data on chronic schizophrenic patients with present data, we hypothesise that FES patients are at the stage that leads to a stable, pathological state of metabolism.

Biomarkers for attention-deficit/hyperactivity disorder (ADHD). A consensus report of the WFSBP task force on biological markers and the World Federation of ADHD.

OBJECTIVE: Psychiatric "nosology" is largely based on clinical phenomenology using convention-based diagnostic systems not necessarily reflecting neurobiological pathomechanisms. While progress has been made regarding its molecular biology and neuropathology, the phenotypic characterization of ADHD has not improved. Thus, validated biomarkers, more directly linked to the underlying pathology, could constitute an objective measure for the condition. METHOD: The task force on biological markers of the World Federation of Societies of Biological Psychiatry (WFSBP) and the World Federation of ADHD commissioned this paper to develop a consensus report on potential biomarkers of ADHD. The criteria for biomarker-candidate evaluation were: (1) sensitivity >80%, (2) specificity >80%, (3) the candidate is reliable, reproducible, inexpensive, non-invasive, easy to use, and (4) confirmed by at least two independent studies in peer-reviewed journals conducted by qualified investigators. RESULTS: No reliable ADHD biomarker has been described to date, but some promising candidates (e.g., olfactory sensitivity, substantial echogenicity) exist. A problem in the development of ADHD markers is sample heterogeneity due to aetiological and phenotypic complexity and age-dependent co-morbidities. CONCLUSIONS: Most likely, no single ADHD biomarker can be identified. However, the use of a combination of markers may help to reduce heterogeneity and to identify homogeneous subtypes of ADHD.

Antidepressant action of tianeptine is connected with acceleration of serotonin turnover in the synapse: a hypothesis.

Based on the results of our investigation of patients with anxious depression under the treatment with serotonergic antidepressants with different mechanism of action on serotonin reuptake we, the first time in the literature, propose the hypothesis about neurochemical mechanism of tianeptine action. According to this hypothesis tianeptine not only activates serotonin reuptake into the synaptic ending but also activates its release from the ending into the synaptic cleft thus accelerating serotonin turnover rate in the synapse. Proposed mechanism mainly refers the first, acute phase of its action directed to the normalization of serotonergic neurotransmission.

Schizophrenia: from the brain to peripheral markers. A consensus paper of the WFSBP task force on biological markers.

Objective. The phenotypic complexity, together with the multifarious nature of the so-called "schizophrenic psychoses", limits our ability to form a simple and logical biologically based hypothesis for the disease group. Biological markers are defined as biochemical, physiological or anatomical traits that are specific to particular conditions. An important aim of biomarker discovery is the detection of disease correlates that can be used as diagnostic tools. Method. A selective review of the WFSBP Task Force on Biological Markers in schizophrenia is provided from the central nervous system to phenotypes, functional brain systems, chromosomal loci with potential genetic markers to the peripheral systems. Results. A number of biological measures have been proposed to be correlated with schizophrenia. At present, not a single biological trait in schizophrenia is available which achieves sufficient specificity, selectivity and is based on causal pathology and predictive validity to be recommended as diagnostic marker. Conclusions. With the emergence of new technologies and rigorous phenotypic subclassification the identification of genetic bases and assessment of dynamic disease related alterations will hopefully come to a new stage in the complex field of psychiatric research.

Biochemical profile in patients with anxious depression under the treatment with serotonergic antidepressants with different mechanisms of action.

The pharmacodynamics of serotonergic antidepressants that differentially influence serotonin reuptake transporters is poorly investigated. The aim of this study was to compare the biochemical profiles in patients with anxious depression under the treatment with tianeptine, a serotonin reuptake enhancer, and sertraline, a selective serotonin reuptake inhibitor. Platelet monoamine oxidase (MAO) and serum amine oxidase (AO) activities, concentration of middle-mass endotoxic molecules (MMEM) and parameters that characterize the functional properties of serum albumin were investigated in 43 patients with anxious depression (ICD-10: F 32.1 and F 33.1). It was established that, in comparison with healthy controls, patients with anxious depression were characterized by the significant increase in MAO activity (by 95%), MMEM concentration (by 86%), and a significant decrease in AO activity (by 43%) and also in functional albumin activity. The results of the study show that both tianeptine and sertraline are equally effective in the treatment of anxious depression. The present biochemical investigation, however, suggests that the underlying biochemical changes are more complete following tianeptine treatment.

Changes in urinary monoamine excretion in hyperkinetic children.

The pathogenetic mechanisms of hyperkinetic syndrome are not clear and need further investigation. The aim of the study was to find certain features of monoamine metabolism that are characteristic of children with hyperkinetic syndrome (HKS) with special regard to different degrees of severity (i.e. mild HKS and severe HKS ). The levels of L-dopa, dopamine, noradrenaline, adrenaline, homovanillic, vanillylmandelic and 5-hydroxyindoleacetic acids were measured in daily urine of children (7-11 years old) with mild and severe HKS using fluorimetric and chromatographic methods. Severe HKS was characterized by a significant increase of L-dopa (by 186%), dopamine (by 201%) and adrenaline (by 160%) excretion but an unchanged excretion of noradrenaline compared with those with mild HKS. The study revealed principle differences in monoamine metabolism between the mild and severe forms of HKS which may be of importance in deciding different pharmacotherapeutic approaches to use in patients with HKS of differing severity.