[The effect of antipsychotic drug on monoamine receptors in peripheral blood mononuclear cells: affinity linked mechanism]. / Vliianie antipsikhoticheskikh preparatov na retseptory monoaminov mononuklearnykh kletok perifericheskoi krovi: affinitet-stseplennyi mekhanizm.

Schizophrenia is one of the most serious and common mental disorders, which is characterized by high levels of pathogenic heterogeneity as well as neuroimmune abnormalities, which require treatment with antipsychotic drugs. Monoamines are one of the key neurotransmitters which play an important role in neuroimmune interactions of the human organism. We suggest that the quantity of the monoamine receptors on mononuclear cells of the peripheral blood (PBMCs) can be associated with the cytokine profile of patients. With this quantity being a key component of the mental status correction mechanism in antipsychotic therapy. In this study we measured cytokine levels (IL-6, IL-1b and TGF-b) in blood serum, the protein expression status of the serotonin receptor 5HTR2A and the dopamine receptors D1 (DRD1), DRD2, DRD3 in PBMCs of drug-naive, first episode schizophrenia patients before and after the treatment with olanzapine and haloperidol. This study has shown for the first time that the antipsychotic therapy leads to a decrease in protein levels of monoamine receptors in PBMCs associated with the affinity of the drug used. Blood cytokine levels were significantly higher in serum from studied patients as compared with the reference values. The antipsychotic-linked change of the TGF-b production caused by the therapy is probably associated with the reduction of various monoamine receptors. The relationship between the psychopathological status and the protein level of 5THR2A suggests that the amount of 5HTR2A may serve as a potential biomarker for the personalized appointment of the antipsychotic therapy.

Potential diagnostic markers of olanzapine efficiency for acute psychosis: a focus on peripheral biogenic amines.

BACKGROUND: Biomarkers are now widely used in many fields of medicine, and the identification of biomarkers that predict antipsychotic efficacy and adverse reactions is a growing area of psychiatric research. Monoamine molecules of the peripheral bloodstream are possible prospective biomarkers based on a growing body of evidence indicating that they may reflect specific changes in neurotransmitters in the brain. The aim of this study was to detect peripheral biogenic amine indicators of patients with acute psychosis and to test the correlations between the biological measures studied and the psychopathological status of the patients. METHODS: This research included 60 patients with acute psychosis treated with olanzapine (n = 30) or haloperidol (n = 30). Here, we measured biogenic amine indicators, including mRNA levels of dopamine receptor D4 (DRD4) and the serotonin 2A receptor (5HTR2A), in peripheral blood mononuclear cells (PBMCs) using quantitative real-time polymerase chain reaction and serum dopamine concentrations by enzyme linked immunosorbent assay (ELISA). Psychopathological status was evaluated using psychometric scales. The assessments were conducted prior to and after 14 and 28 days of treatment. RESULTS: The administration of haloperidol, but not olanzapine, up-regulated 5HTR2A mRNA in a linear manner, albeit without statistical significance (p = 0.052). Both drugs had non-significant effects on DRD4 mRNA levels. Nevertheless, a positive correlation was found between DRD4 and 5HTR2A mRNA levels over a longitudinal trajectory, suggesting co-expression of the two genes. A significant positive correlation was observed between 5HTR2A mRNA levels and total Positive and Negative Syndrome Scale (PANSS) scores in both groups of patients before treatment. A significant correlation between baseline 5HTR2A mRNA levels and PANSS scores on days 14 and 28 of treatment remained for patients treated with olanzapine only. Moreover, a significant positive correlation was observed between blood serum dopamine levels and scores on extrapyramidal symptom scales in the olanzapine group. CONCLUSIONS: The DRD4 and 5HTR2A genes are co-expressed in PBMCs during antipsychotic administration. Despite a correlation between the studied biogenic amine indicators and the psychopathological status of patients, reliable biomarkers of treatment response could not be determined.

[Dopamine neurotransmission of peripheral blood lymphocytes is a potential biomarker of psychiatric and neurological disorders].

Current literature on a role of dopamine in the development of mental and neurological disorders suggests that the discovery of endogenous dopamine in peripheral blood lymphocytes gave rise to a new line of research. Dopamine receptors are not only found on cells of the innate immune response (nonspecific), but also on cells of adaptive immune response (specific): T and B lymphocytes. These facts bring a new evidence of interrelationships between the peripheral immune system, neuroinflammation and neurodegeneration and suggest new ways for investigation of the pathogenesis of different mental and neurological disorders, in particular Parkinson's disease, Alzheimer's disease and schizophrenia. There is strong evidence that ligands of dopamine receptors can change the expression of coding genes both in central neurons and in peripheral cells. Thus, peripheral blood lymphocytes may prove a cellular tool to identify dopamine transmission disturbances in neuropsychiatric diseases, as well as to monitor the effects of pharmacological treatment.

[Pharmacogenetic-based risk assessment of antipsychotic-induced extrapyramidal symptoms].

"Typical" antipsychotics remain the wide-prescribed drugs in modern psychiatry. But these drugs are associated with development of extrapyramidal symptoms (EPS). Preventive methods of EPS are actively developed and they concentrate on personalized approach. The method of taking into account genetic characteristics of patient for prescribing of treatment was proven as effective in cardiology, oncology, HIV-medicine. In this review the modern state of pharmacogenetic research of antipsychotic-induced EPS are considered. There are pharmacokinetic and pharmacodynamic factors which impact on adverse effects. Pharmacokinetic factors are the most well-studied to date, these include genetic polymorphisms of genes of cytochrome P450. However, evidence base while does not allow to do the significant prognosis of development of EPS based on genetic testing of CYP2D6 and CYP7A2 polymorphisms. Genes of pharmacodynamics factors, which realize the EPS during antipsychotic treatment, are the wide field for research. In separate part of review research of such systems as dopaminergic, serotonergic, adrenergic, glutamatergic, GABAergic, BDNF were analyzed. The role of oxidative stress factors in the pathogenesis of antipsychotic-induced EPS was enough detailed considered. The system of those factors may be used for personalized risk assessment of antipsychotics' safety in the future. Although there were numerous studies, the pharmacogenetic-based prevention of EPS before prescribing of antipsychotics was not introduced. However, it is possible to distinguish the most perspectives markers for further research. Furthermore, brief review of new candidate genes provides here, but only preliminary results were published. The main problem of the field is the lack of high- quality studies. Moreover, the several results were not replicated in repeat studies. The pharmacogenetic-based research must be standardized by ethnicity of patients. But there is the ethnical misbalance in world literature. These facts explain why the introduction of pharmacogenetic testing for risk assessment of antipsychotic-induced EPS is so difficult to achieve.