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Biological markers in psychiatric disorders

In spite of the progress in the methodological approaches, some biochemical processes in the human brain still remain unresolved, particularly those involved in the ethiology and treatment of psychiatric disorders. The investigations of the biochemical processes in the human brain in vivo are limited due to the ethical reasons. There are few direct methods available, including analysis of brain tissue obtained during neurosurgery, biopsy and post mortem. The results of tissue analysis are dependent on the interval between death and tissue sampling and could be infuenced by previous antipsychotic therapy. Nowadays, the most promissing methods for the in vivo studies in humans are those based on positron emission tomography (PET). In these methods short-lived positron emitters are used for the in vivo measurement of pathophysiological variables in human brain. Using PET and alpha-11Cmethyl-L-tryptophan, as a tryptophan analog, the sex difference in the rate of serotonin synthesis was determined for the first time in the human brain in vivo (Nishizawa et al., 1997). The rate of serotonin synthesis was significantly higher in healthy male than in healthy female persons, suggesting that this difference may be a factor relevant to the lower incidence of depressive disorders in males.This PET method with alpha-11Cmethyl-L-tryptophan could be useful in the clinical studies for identifying regional differences in the rates of serotonin synthesis between patients and healthy controls, and could be also applied in the evaluation of individual differences in the subjects treated with psychotropic drugs. Recently, a reduced binding of 18F-fluoroethylspiperone (18F-FESP) to 5-HT2A receptors in cortices of drug-free depressed patients in vivo has been found (Messa et al., 2003). Since alteration in 5-HT2A receptors disappeared after treatment with antidepressent drug paroxetine, it has been suggested that 18F-FESP binding may represent a state marker of depression. Since PET studies are expensive and require special equipment, there are extensive search for the suitable, easy obtainable peripheral markers of biochemical processes in the brain. Literatura data suggest that cerebrospinal fluid, blood or urine concentrations of neurotransmmitters, their metabolites and enzymes involved in their synthesis or metabolism, as well as neurotransmitter receptors on blood cells, can be used as the indirect peripheral markers. The calcium binding protein S-100B is produced by astroglia cells of the central nervous system. It plays a role in the axonal growth and synaptogenesis during development and synaptic remodeling (Donato, 2001). Since it is a small molecule, S-100B easily crosses the blood-brain barriere and could be determined in cerebrospinal fluid and serum. It has been suggested that S-100B could be used as a peripheral marker for the brain injury, but also for psychiatric disorders (Manev and Manev, 2001), like schizophrenia (Wiesmann et al., 1999) and depression (Machado-Vieira, 2002). It is widely accepted that blood platelets can be used as a peripheral model for the central serotonergic neurons. Uptake, storage and release of serotonin into platelets and platelet monoamine oxidase type B activity resemble the corresponding counterparts and biological processes in the central serotonergic neurons. Moreover, on the platelet membrane, there are 5-HT2 receptors (Andres et al., 1993), alpha2-adrenergic receptors (Piletz et al., 1986) and binding sites for 3Himipramine and 3H-paroxetine, which have pharmacologic and kinetic characteristics similar to the equivalent central nervous receptors and binding sites (Stahl, 1985). It has been suggested that the presence of psychotic features in subtypes of schizophrenia and depression is correlated with the presence of increased levels of platelet serotonin (Mück-Šeler et al., 1991). Recently published results revealed that pretreatment platelet serotonin concentrations might predict therapeutic outcome to paroxetine (Mück-Šeler et al., 2002). Blood platelets represent also an important source of peripheral amyloid precursor protein (APP) isoforms, that are equivalent to those found in the brain. Literatura data suggest that APP isoforms are associated with the pathogenesis and progress of Alzheimer disease. The levels of platelet APP isoforms can be considered as a potential peripheral marker of Alzheimer disease, but not of other types of dementia (Di Luca et al., 2000). The development of molecular biology opens a new approach in the investigation of biological markers in psychiatric disorders. The purpose of molecular genetic studies of psychiatric disorders is to identify the correlation between specific polymorphism of gene(s) and mental disorders, with the aim to develop a predictive, diagnostic tests for psychiatric disoders, as well as to identify the targets for therapeutic drugs (Sher, 2001). Recently, the association of genes encoding proteins implicated in serotonergic metabolism with manic-depressive illness and suicidal behaviour has been described (Mann et al., 2001).

Central nervous system; blood platelets; proteins; receptors; molecular psychiatry

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