[Pharmacogenomic and pharmacometabolomic biomarkers of the efficacy and safety of antidepressants: focus on selective serotonin reuptake inhibitors]. / Farmakogenomnye i farmakometabolomnye biomarkery effektivnosti i bezopasnosti antidepressantov: fokus na selektivnye ingibitory obratnogo zakhvata serotonina.

The efficacy and safety of psychopharmacotherapy with antidepressants is of great medical importance. The search for clinical and biological predictors for choosing the optimal psychopharmacotherapy with antidepressants is actively underway all over the world. Research is mainly devoted to searching for associations of polymorphic gene variants with the efficacy and safety of therapy. However, information about a patient's genetic polymorphism is often insufficient to predict the efficacy and safety of a drug. Modern research on the personalization of pharmacotherapy should include, in addition to genetic, phenotypic biomarkers. This is important because genotyping, for example, cannot accurately predict the actual metabolic activity of an isoenzyme. To personalize therapy, a combination of methods is required to obtain the most complete profile of the efficacy and safety of the drug. Successful treatment of depression remains a challenge, and inter-individual differences in response to antidepressants are common. About half of patients with depressive disorders do not respond to the first attempt at antidepressant therapy. Serious side-effects of antidepressant pharmacotherapy and discontinuation of treatment due to their intolerance are associated with ineffective therapy. This review presents the results of the latest studies of «omics¼ biomarkers of the efficacy and safety of antidepressants.

[The role of genetic factors in the development of suicidal behavior in individuals with dependence on synthetic cathinones]. / Rol' geneticheskikh faktorov v razvitii suitsidal'nogo povedeniya u lits s zavisimost'yu ot sinteticheskikh katinonov.

OBJECTIVE: To identify polymorphisms in the genes of dopaminergic and serotonergic systems associated with the risk of suicidal behavior in individuals with dependence on synthetic cathinones. MATERIAL AND METHODS: One hundred and eighty-two men with the diagnosis of Substance dependence (ICD-10 F15) tested positive for metabolites of synthetic cathinones (a-PVP, MDPV) in the urine were studied. Genotyping was performed for rs1800497 DRD2, rs4646984 DRD4, VNTR 40 b.p. SLC6A3, rs27072 SLC6A3, rs6313 HTR2A and rs6296 HTR1B using PCR and RFLP technique. RESULTS AND CONCLUSION: It was found that the genes of the serotonergic system HTR2A and HTR1B are predictors of the development of some endophenotypes of suicidal behavior in individuals with dependence on synthetic cathinones.

[The combined effect of genetic factors and attention deficit hyperactivity disorder on the development of dependence on synthetic cannabinoids]. / Sochetannoe vliianie geneticheskikh faktorov i sindroma defitsita vnimaniia s giperaktivnost'iu na razvitie zavisimosti ot sinteticheskikh kannabinoidov.

AIM: To develop a model of assessment of individual risk of dependence on synthetic cannabinoids based on genetic factors and diagnosis of attention deficit hyperactivity disorder (ADHD). MATERIAL AND METHODS: The study included 146 male adolescents using synthetic cannabinoids and 136 healthy people. The genetic study considered the combination of dependence on synthetic cannabinoids and ADHD. Six polymorphisms in the genes of dopaminergic and serotonergic systems were genotyped. RESULTS AND CONCLUSION: In general, the results of this work confirm the important role of the dopaminergic and serotonergic systems in the pathogenesis of substance use disorders, and the significance of changes in the nucleotide sequences of DRD2, SLC6A3, HTR2A genes in the development of dependence on synthetic cannabinoids with ADHD.

[Brain neurotransmitter systems gene Polymorphism: the Search for pharmacogenetic markers of efficacy of haloperidol in Russians and Tatars].

Antipsychotics are the main drugs for the treatment of severe mental illness--schizophrenia affects about 1% of the population. The mechanism of action of neuroleptics is still up to the end. Several studies in the field of pharmacogenetics confirm enourmous influence of several neurotransmitter systems in the brain on the efficiency and the development of side effects. In this paper, we analyzed the association of nine polymorphic variants of five genes of dopaminergic and serotonergic systems DRD4, HTR2A, TPH1, SLC18A1, COMT in Russian and Tatars patients living in the Republic of Bashkortostan (RB) with the efficiency of a typical antipsychotic haloperidol on the scale of positive and negative systems of PANSS. The study established pharmacogenetic markers of increased and decreased effectiveness of therapy with haloperidol in the treatment groups. The results of this study confirm the importance of changes in the nucleotide sequences of the studied genes of the serotoninergic and dopaminergic systems (HTR2A, TPH1, SLC18A1 COMT, DRD4) in the formation of individual sensitivity to haloperidol. The results of our work considered as preliminary contact, requires an increase in the number of samples studied.

[The Role of Neurotrophins and Neurexins Genes in the Risk of Paranoid Schizophrenia in Russians and Tatars].

Schizophrenia affects about 1% of the population. Its etiology is not fully understood. Environmental conditions certainly contribute to the development of schizophrenia, but the determining factor is genetic predisposition: the coefficient of heritability of schizophrenia is about 80%, which is typical for the most highly heritable multifactorial diseases. Polymorphic loci of genes of enzymes and receptors involved in the processes of neuroprotection and neurotrophia play significant role in the development of this disease. In this paper we investigated 48 polymorphic variants of genes of the neurotrophins and neurexins family (BDNF, NTRK2, NTRK3, NGF, NXPH1, and NRXN1) in Russian and Tatar cases and in a control group living in the Republic of Bashkortostan. The results of this study confirm the important role of neurotrophin and neurexin genes in paranoid schizophrenia development.

[The association of polymorphisms in SLC18A1, TPH1 and RELN genes with risk of paranoid schizophrenia].

We have developed a biochip for the analysis of polymorphisms in candidate genes for schizophrenia: DISC1, RELN, ZNF804A, PLXNA2, COMT, SLC18A41, CACNA1C, ANK3, TPH1, PLAA and SNAP-25. Using biochip the allele and genotype frequencies in 198 patients with schizophrenia and 192 healthy individuals have been obtained. For SLC18A1 polymorphism rs2270641 A>C, the frequencies of A allele (p = 0.007) and AA genotype (p = 0.002) were lower in patients compared with healthy individuals. A significant association was found between AA genotype (p = 0.036) of the TPH1 polymorphism rs1800532 C>A and schizophrenia. The C allele (p = 0.039) of the RELNpolymorphism rs7341475 C>T were lower in patients with schizophrenia compared with healthy individuals in a tatar population. Genotype AA of the TPH1 polymorphism rs1800532 C>A were more frequent in patients with schizophrenia compared with healthy individuals. Ithas been shown that the C allele (p = 0.0001) and GC (p = = 0.0001) genotype of the PLXNA2 polymorphism rs1327175 G>C are associated with the family history in patients with paranoid schizophrenia. The obtained data suggest that SLC18A1, TPH1 and RELN gene polymorphisms are associated with the risk of paranoid schizophrenia.

[Glutamate receptors genes polymorphism and the risk of paranoid schizophrenia in Russians and tatars from the Republic of Bashkortostan].

Schizophrenia is a severe mental disorder that affects about 1% of the world population, leading to disability and social exclusion. Glutamatergic neurotransmission is a violation of one of the main hypotheses put forward to explain the neurobiological mechanisms of schizophrenia. Post mortem studies have found changes in the degree of affinity glutamate receptors, their transcription, and altered expression of their subunits in the prefrontal cortex, hippocampus, and thalamus in patients with schizophrenia. As a result of genetic studies of gene family encoding ionotropic AMPA and kainate glutamate receptors in schizophrenia, ambiguous results were received. The association of polymorphic variants of genes GRIA2 and GRIK2 with paranoid schizophrenia and response to therapy with haloperidol in Russian and Tatar of the Republic of Bashkortostan was conducted in the present study. DNA samples of 257 patients with paranoid schizophrenia and of 349 healthy controls of Russian and Tatar ethnic group living in the Republic of Bashkortostan were involved into the present study. In the result of the present study: (1) high risk genetic markers of paranoid schizophrenia (PSZ) were obtained: in Russians-GR4IA2*CCC (OR = 9.60) and in Tatars-GRIK2*ATG (OR = 3.5), GRIK2*TGG (OR = 3.12) (2) The following low risk genetic markers of PSZ were revealed: in Tatars-GRIA2*T/T (rs43025506) of GRIA2 gene (OR = 0.34); in Russians.- GRIA2*CCT (OR = 0.481). (3) Genetic markers of low haloperido! treatment efficacy in respect of negative and positive symptoms GRIK2*T/T (rs2227281) of GRIK2 gene and GRAL42*C/C in Russians, GRIK2*A/A (rs995640) of GRIK2 gene in Tatars. (4) Genetic markers of low haloperidol treatment efficacy in respect of positive symptoms GRL42*C/C in Russians. The results of the present study support the hypothesis of the involvement of glutamate receptor genes in schizophrenia pathway. Considerable inter-ethnic'diversity of genetic risk factors for this disease was revealed.

[Association polymorphic variants of GRIN2B gene with paranoid schizophrenia and response to common neuroleptics in Russians and Tatars from Bashkortostan Republic].

An analysis of the association of paranoid schizophrenia seeking with polymorphic variants of GRIN2B gene was performed in order to identify genetic risk factors of disease development and genetic markers of the response to therapy by neuroleptics in Russian and Tatar patients from Bashkortostan Republic (BB). In the course of the analysis, we revealed the following: 1) genetic markers of increased risk of developing paranoid schizophrenia in various ethnic groups, including, in Tatars, the GRIN2B* T/*Tgenotype (p = 0.003; OR = 2.33) and GRIN2B*T allele (p = 0.001; OR = 2.36), rs1805247; in Russians, the GRIN2B*T/*T genotype (p = 0.038; OR = 2.12) and GRIN2B* T allele (p = 0.028; OR = 2.03), rs1805247, genotype GRIN2B*A/*A (p = 0.042; OR = 2.12), rs1805476; 2) genetic markers of the reduced risk of developing paranoid schizophrenia; 3) genetic markers of therapy response and the risk of side effects development during neuroleptics (haloperidol) treatment in Bashkortostan. The significant interethnic diversity of genetic factors related to the risk of this disease development was noted.

[Polymorphism of RGS2 gene: genetic markers of risk for schizophrenia and pharmacogenetic markers of typical neuroleptics efficiency].

Schizophrenia is a common psychiatric disorder affecting about 1% of the general population. Several lines of evidence indicate that Regulator of G Protein Signaling 2 (RGS2) contributes to schizophrenia vulnerability because it modulates signal transduction of neurotransmitter receptors that play a role in the pathogenesis of schizophrenia. A number of studies have shown an association of polymor- phic loci RGS2 gene with the occurrence of extrapyramidal symptoms induced by neuroleptics. DNA samples of 258 patients with paranoid schizophrenia and of 263 healthy controls of Russian and Tatar ethnic group living in the Republic of Bashkortostan were involved into the present study. In the result of the present study low risk genetic markers; high risk genetic markers of paranoid schizophrenia RGS2*G/*G (rs2746071) in Russians (p = 0.001; OR = 4.08) and in Tatars (p = 0.000; OR = 4.88); allele.RGS2*G in Russians (p = 0.00003; OR = 2.37) and Tatars (p = 0.000; OR = 2.51), high risk genetic markers of parkinsonism induced by haloperidol: RGS2*T/*T(rs2746073), RGS2*C/*C (rs4606), RGS2*A/*A (rs2746071) in Rus- sians, genetic markers of treatment efficacy in Tatars were obtained in individuals from the Republic of Bash- kortostan; considerable inter-ethnic diversity of genetic risk factors for this disease was revealed The results of this study are consistent previous results and support the hypothesis that polymorphic loci RGS2 gene associated with risk of extrapyramidal symptoms induced by typicalneuroleptics-haloperidol, and are involved in schizophrenia pathway.

[An association study of polymorphisms in HTR2A, BDNF and SLC6A4 genes with paranoid schizophrenia and suicidal behavior].

We have developed a biochip for the analysis of candidate genes for schizophrenia. Using this biochip, allele and genotype frequencies for the polymorphisms of HTR2A, BDNF and SLC6A4 genes in 198 patients with schizophrenia and 192 healthy individuals have been obtained. The allele T of the HTR2A polymorphism rs6314 was identified as protective against the development of paranoid schizophrenia (p=0,014). An analysis of gene-gene interactions using the Multifactor-Dimensionality Reduction (MDR) algorithm has shown a statistically significant association of combined genotypes rs6311 G/-, rs6313 C/-, rs6314 C/C, rs7997012 G/- with the disease (p=0.019). Also it has been shown that the G/G genotype of the polymorphism rs6311 (p=0.013) and the C/C genotype of the polymorphism rs6313 (p=0.008) in the HTR2A gene are associated with the suicide attempt in schizophrenic patients. Correspondingly, an A allele, А/- genotypes of the polymorphism rs6311 G>A and a T allele, T/- genotypes of the polymorphism rs6313 C>T were found to be less frequent in schizophrenic patients with a history of suicide attempt than in schizophrenic patients without a history of suicide attempt, thus suggesting their protective role in the development of suicidal behavior. The results confirm the hypothesis that the HTR2A plays an important role in the etiology of schizophrenia and suicidal behavior.

[Analysis of clusterin gene (CLU/APOJ) polymorphism in Alzheimer's disease patients and in normal cohorts from Russian populations].

Three genes mutations in which cause familial forms of Alzheimer's disease are known to date:PSEN1, PSEN2 and APP; and APOE gene polymorphism is a strong risk factor for Alzheimer's disease. We have evaluated allele and genotype frequency distribution of rs11136000 polymorphism in clusterin (CLU) gene (or apolipoprotein J, APOJ) in populations of three Russian regions and i nAlzheimhner's diseasepatients. Genome-wideassociation studies in samples from several European populations have recently revealed highly significant association o fCLU gene with AD (p = 8.5 x 10(-10)). We found no differences in allele and genotype frequencies of rs11136000 between populations from Moscow, Ural and Siberia regions. The allele frequencies are close to those in European populations. The genetic association analysis in cohort of Alzheimer's disease patients and normal individuals (>500 individuals ineach group) revealed no significant association of the rs11136000 polymorphism in CLU with Alzheimer's disease in Russian populations. Although our resultsdo not confirm the role of CLU gene as a majorgenetic factor forcommon form of Alzheimer's disease, the data do not rule out the possibility of modest effect of CLU and interaction between CLU and APOE genotypes in etiology of Alzheimer's disease.

[Association of several polymorphic loci of serotoninergic genes with unipolar depression].

Serotoninergic system is one of the major brain neurotransmitter systems that is involved in the development of depression disorders. Regulatory genes of this system are the principle candidate genes predisposing to unipolar depression. Using PCR-RFLP analysis, we have conducted a study of polymorphic loci of several genes of this system: C1019G of serotonin receptor 1A gene, (HTR1A); A438G of serotonin receptor 2A gene, (HTR2A); G861C of serotonin receptor 1B gene, (HTR1B); Stin2VNTR and 5-HTTLPR of serotonin transporter gene (SLC6A4) in patients with unipolar depression among ethnic Tatars and Russians. The results of the study suggest that genotype 10/10 of the SLC6A4 gene as well as genotype G/G and allele G of the HTR2A gene can predispose for increased risk of unipolar depression development in ethnic Russians. In contrast, genotype 12/10 of the SLC6A4 gene is a marker of low risk of the disease development in both ethnic groups.

[Association study of NcoI and TaqI A dopamine receptor D2 gene polymorphism in opium addicts]. / Analiz assotsiatsii NcoI and Taq A polimorfizma gena D2 retseptora dofamina s opiinoi narkomaniei.

The N2/N2 (NcoI) genotype of DRD2 gene is shown to be a marker of resistance to opium addiction, the N1/N1 genotype being considered as a risk marker for the disorder. The N1 allele was associated with opium addiction in Russian patients aged 16 years and younger at drug using onset. In Tatars, an association was found between the N1 allele and a risk of opium addiction development over 16 years of age. The N2/N2 genotype proved to be a marker of resistance to opium addiction in Tatars over 16 years of age at drug using onset. No association was found between TaqI A DRD2 polymorphism and opium addiction in the Russians and the Tatars.

[VNTR polymorphisms of the serotonin transporter and dopamine transporter genes in male opiate addicts]. / Otsenka VNTR-polimorfizma v genakh perenoschikov serotonina i dofamina u muzhchin s opiinoi narkomaniei.

VNTR polymorphisms of the serotonin transporter (hSERT) and dopamine transporter (DAT1) gene were studied in male opiate addicts. Samples of ethnic Russians and ethnic Tatars did not differ in genotype and allele frequencies. Homozygosity at hSERT (especially 10/10) was associated with early opiate addiction, while genotype 12/10 proved to be protective. In the case of DAT1, genotype 9/9 was associated with early opiate addiction. The combination of hSERT genotype 10/10 with DAT1 genotype 10/10 was shown to be a risk factor of opiate abuse under 16 years of age.