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Personalized Psychiatry and Neurology

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Vol 1, No 1 (2021)

LETTER 

REVIEW 

3-10 382
Abstract

Antipsychotics (APs) are the base of schizophrenia pharmacotherapy. There are large individual differences in effectiveness and adverse drug reactions (ADRs) of APs. There is an urgent need for a personalized approach to the therapy. Genetic factors are predisposed to patient's response to APs therapy. Pharmacogenetic studies of APs have examined a number of single nucleotide variants (SNVs), of which only a few were associated with therapeutic efficacy and ADRs development. However, only a limited number of these results have clinical applications in psychiatry. Nowadays, it seems promising to study SNVs of leptin system genes (LEP, LEPR) and neuropeptide Y (NRY). Studying the mechanisms of APs-induced weight growth will allow their transmission to a personalized approach. It will help psychiatrists in patients' selection for the APs therapy. This will increase safety and effectiveness of the therapy, improve the quality of life and adherence to therapy in patients with schizophrenia.

11-17 315
Abstract

Antipsychotics (AP) is a group of psychotropic drugs for the treatment of mental disorders, in particular schizophrenia. In the mid-1950s, the first AP was synthesized (known as chlorpromazine (CPZ)). This drug has revolutionized the treatment of psychotic disorders. This drug, in addition to the antipsychotic effect, caused severe adverse drug reactions in patients, in particular from the neurological system, such as AP-induced extrapyramidal syndrome (EPS) — chlorpromazine-in-duced parkinsonism (CPZ-IP). CPZ-IP characterized by the occurrence of motor disorders. CPZ-IP is as a result of damage to the basal ganglia and subcortical-thalamic connections. Drug-induced EPS is subdivided into primary and secondary. Among the primary EPS, drug-IP is the most common (the leading form of secondary parkinsonism). Pharmacogenetic markers of CPZ safety are being actively studied. Some pharmacogenetic markers of therapy safety have been established: single nucleotide variants/polymorphisms of candidate genes for dopaminergic receptors D2 and D3 (DRD2 (rs1799732 (-141C Ins/Del)), DRD3 (rs6280 (Ser9Gly)), laforine phosphatase (EPM2A (rs1415744 (C/T)).

18-36 491
Abstract

(1) Introduction: An imbalance of the genetically determined cytokine response plays a key role in the etiology of ENT-associated encephalitis. In recent years, an attempt has been made to evaluatethe prognostic role of chronic pathology of the paranasal sinuses in the development of acute, subacute and chronic encephalitis and meningitis, which in clinical practice are manifested both as cerebral and focal neurological symptoms and as mental disorders: from borderline to psychotic ones. The problem requires a multidisciplinary approach on the part of the specialists in the following clinical disciplines: neurology (as well as neurobiology), psychiatry, immunology, experimental medicine, otorhinolaryngology, and pharmacogenetics. The solution of this problem is possible with the involvement of preventive and personalized medicine.

(2) The purpose: Evaluation the prognostic role of genetic polymorphisms of pro- and antiinflammatory cytokines in the development of ENT-associated encephalitis.

(3) Materials and Methods: We conducted a keyword-based analysis of the English and Russian-language articles published within the past 30 years (from 1988 to 2018). The following databases were used in the study: PubMed, MedLine, Web of Science Core Collection (Clarivate Analytics), Web Science, Russian Science Citation Index, Scopus, Scientific Research, Google Scholar, Oxford Press, and eLibrary.

(4) Results: In a number of the analyzed works, regardless of the causative agent and viral load, an increased level of pro-inflammatory cytokine production was noted in patients with more severe disease progression, neurological complications and unfavorable outcomes, both in viral encephalitis and in bacterial one. Based on this, 30 single nucleotide variants (SNV), their influence on the expression of pro- and anti-inflammatory cytokine genes, as well as their predictor role in the development of ENT-associated encephalitis were analyzed. Due to the nature of the systemic immune response, the analysis included both cerebral and extracerebral pathology-associated SNV. The inconsistency of the previously obtained results was noted, an attempt to explain this phenomenon was made. The analysis of the dynamics and geography of publications on the stated topic was made, the leading Russian scientific centers in the field were defined. The most promising SNV for further studies were identified.

(5) Conclusion: The risk of developing ENT-associated encephalitis is associated with a genetically determined status of the cytokine response and its regulation. Studies of the association of various SNV of genes encoding pro- and anti-inflammatory cytokines in the Russian Federation need to be continued.

37-45 448
Abstract

Low back pain (LBP) is an important interdisciplinary medical problem, in the development of which various molecular genetics, pathomorphological and pathobiomechanical mechanisms play a role. Intervertebral disc degeneration (IVDD), facet joints arthrosis and myofascial syndrome are the most important pathological processes associated with chronic lower back pain in adults. The nitric oxide (NO) system may play one of the key roles in the development of LBP and its chronicity. (1): Background: The review of publications which are devoted to changes in the NO system in patients with LBP. (2): Materials: We have carried out a search for Russian-language and English-language full-text articles published in e-Library, PubMed, Oxford Press, Clinical Case, Springer, Elsevier, Google Scholar databases. The search was carried out using keywords and their combinations. The search depth was 10 years (2011-2021). (3): Results: Role of NO and various NOsynthase (NOS) isoforms in LBP process demonstrated primarily from animal models to humans. The most studied are the neuronal NOS (nNOS). The role of inducible nose (iNOS) and endothelial (eNOS) - continues to be studied. Associative genetic studies have shown that single nucleotide variants (SNV) of genes encoding all three NOS isoforms (nNOS, NOS1 gene; iNOS, NOS2 gene; eNOS, NOS3 gene) may be associated with chronic LBP. Prospects for the use of NOS inhibitors to modulate the effect of drugs used to treat back pain are discussed. (4): Conclusion: Associative genetic studies of SNV NOS1, NOS2, NOS3 genes are important for understanding genetic predictors of LBP chronicity and development of new personalized pharmacotherapy strategies.

46-53 516
Abstract

Empty sella (ES) is a condition characterized by arachnoid herniation into the sellar fossa which leads to flattening of the pituitary gland against the sellar floor. Besides endocrine disturbances, patients with ESS may also have neuropsychiatric symptoms such as headache, dizziness, seizures, schizophrenia. Typically, ES is not inherited. However, due to the advent of new methods of brain imaging and molecular genetics, the perspective on the genetics of ESS has been changing. The aim of this study is to analyze genome-wide association studies of candidate genes related to the development of ESS in humans. Based on the available studies which have been analyzed, all candidate genes of ESS were divided into 4 groups: group 1 - candidate genes related to ESS, group 2 - candidate genes related to pathways of ESS, group 3 - candidate genes related to cellular components of ESS, group 4 - candidate genes related to biological processes of ESS.

54-63 414
Abstract

Primary headaches are common neurological problem in the world. Migraine (M) and tension type headache (TTH) are the leaders in the structure of primary headaches in the population; (1) Background: The study of the association of single nucleotide variants (SNVs) of MTHFR (meth-ylenetetrahydrofolate reductase) and HTR2C (5-Hydroxytryptamine Receptor 2C) genes with M and TTH development in the European population in Siberia (Russia); (2) Methods: 192 adults were examined: 82 (42.7%) males and 110 (57.3%) females. Control group: 81 healthy adults, median age 49.5 [36; 59] years; 53 (66.7%) males and 27 (33.3%) females. Headache group consisted of 111 patients with primary headache, median age 54 [45; 64] years, including two subgroups: subgroup 1 (M) of 39 patients; subgroup 2 (TTH) of 72 patients. Carriage of alleles and genotypes rs1801133 and rs1801131 of the MTHFR gene and rs6318 of the HTR2C gene was determined using PCR-RT by TaqMan allelic discrimination technology; (3) Results: A statistically significant association of the carriage of the A allele rs1801133 of the MTHFR gene with the formation of M (p = 0.025) and TTH (p = 0.022), as well as the GA genotype with the development of TTH (p = 0.024) was revealed. Carriage of the G allele and the TG and GG genotypes of the MTHFR gene, associated with a decreased activity of the MTHFR enzyme, does not affect the development of primary headache. A statistically significant association was revealed between the carriage of the heterozygous GC genotype (rs6318) of the HTR2C gene and the formation of M (p = 0.013); (4) Conclusions: Carriage of the A allele (OR 1.77; 95% CI 1.09-2.89) and the GA genotype (OR 2.24; 95% CI 1.17-4.29) rs1801133 of the MTHFR gene is a risk factor for the development of TTH (p <0.05). Carriage of the A allele rs1801133 of the MTHFR gene is a risk factor for the development of M (OR 1.97; 95% CI 1.08-3.57; p <0.05). Carriage of the variant G allele and rs1801131 GT and GG genotypes associated with reduced activity of the MTHFR enzyme does not affect the development of primary headache. In the control group, the prevalence of the T allele associated with normal enzymatic activity was noted (p = 0.024). Carriage of the heterozygous genotype CG SNV rs6318 of the HTR2C gene increases the risk of developing migraine by 3.6 times.

64-72 360
Abstract

Sports injuries prevention is one of the key issues of the training process and reducing the risk of developing anxiety and depressive disorders in professional athletes. One of peculiarities of sports injuries is the loss of the ability to train in view of the tendon-ligamentous apparatus integrity, joints, muscles or bones violation. In cyclic sports, the most common are injuries to the ankle joint, injuries to muscles and tendons, and sprains. Injuries to ligaments and tendons are the result of multifactorial problems, including the discrepancy between training effects and the genetically determined capabilities of the athlete's body. Sports injuries consequences are determined by complex interactions between the athlete's genotype and environmental factors, in particular training influences. (1) Background: to review scientific articles on the problem of research on candidate genes and single-nucleotide variants (SNVs) of genes associated with muscle, tendon, and ligament injuries in cyclic sports athletes. (2) Methods: a search of articles for the period from 2008 to 2020 was conducted in the databases e-LIBRARY, SCOPUS, Web of Science, Google Scholar, Clinical keys, PubMed using the keywords: personalized medicine, genetics, candidate genes, single-nucleotide variant, polymorphism, muscle, tendon, injury, athlete. (3) Results: Studies have shown that muscle and tendon injuries in cyclical sports athletes are associated with SNV rs1800012, rs1107946 of the COL1A1 gene, SNV rs12722 of the COL5A1 gene, SNV rs679620 of the MMR3 gene, SNV rs2289360 of the ELN gene, SNV rs143383 of the GDF5 gene. The most studied polymorphisms are rs1800012, rs1107946 of the COL1A1 gene, rs12722 of the COL5A1 gene, and rs143383 of the GDF5 gene. The variable results of associative genetic studies and genome-wide studies are most likely due to the racial and ethnic heterogeneity of the samples and differences in the study design. (4) Conclusions: Identification of genetic markers associated with injuries and diseases of the musculoskeletal system, ligamentous apparatus, and the ability of tissue to regenerate can help sports doctors and coaches develop personalized strategies to prevent or reduce muscles, joints, and ligaments diseases in athletes. The translation of these research results into the training and treatment process is important for improving cyclic sports athletes' performance, reducing their professional mala-daptation and anxiety and depressive disorders development risk.

73-83 386
Abstract

(1) Introduction: Quetiapine (QTP) is a dibenzothiazepine derivative, a second generation antipsychotic (AP), which is structurally similar to clozapine. The main indications for use are schizophrenia and depressive disorder. Under manic episodes in bipolar disorder can be used alone or in combination with lithium. The frequency of prescribing QTP is on average 11,987 per 100,000 population, with a positive trend in dynamics: a growth rate of more than 800% within the period 2002 to 2017.

(2) Purpose: The review of studies of pharmacogenetic pharmacokinetic and pharmacogenetic pharmacodynamic markers of QTP efficacy and safety.

(3) Materials and Methods: A search was carried out for publications of the Science Index, PubMed, Web of Science, Springer databases by keywords and their combinations over the last 10 years. In addition, the review includes earlier publications of historical interest. Despite extensive searches of these commonly used databases and search terms, it cannot be ruled out that some publications may have been missed.

(4) Results: The review considers the following pharmacokinetic markers of QTP efficacy and safety: genes are coding isoforms of cytochrome P450 (CYP2D6, CYP2C19, CYP3A4, CYP3A5), P-glycoprotein (ABCB1); pharmacogenetic pharmacodynamic markers of the efficacy and safety of QTP : genes of dopamine receptor isoform (DRD3), dopamine transporter (SCL1A1) and catecholO-methyltransferase (COMT), serotonin receptor isoforms (HTR2C), melanocortin receptor (MC4R), NOTCH protein (NOTCH4), phosphodiesterase 4D (PDE4D), SPoPL protein (SPoPL), multiple EGFlike domain (MEGF10), protocadherin-7 (PCDH7), contactin-associated protein 5 (CNTNAP5) , TRAF2 and NCK-interacting protein kinase (TNIK), spermatogenesis-associated protein 6 (SPATA6L), neurobihin (NBEA), synaptic vesicle protein-2C (SVC2) .

(5) Conclusion: Disclosure of pharmacogenetic markers of pharmacokinetics and pharmacodynamics of QTP efficacy and safety in the treatment of patients with schizophrenia and other psychiatric disorders, may provide a key to developing a strategy for its personalized prevention of adverse grug reactions (ADRs) and therapy strategy in real clinical practice.

93-101 535
Abstract

There is a number of antidepressants (ADs) which prevent reabsorption of neurotransmitters in the body. Known together as reuptake inhibitors, they prevent the reuptake of one or some neurotransmitters so that the majority of them is present and active in the brain. Selective serotonin reuptake inhibitors (SSRIs) work at the expense of specific inhibition of serotonin reuptake. Such new SSRIs fluoxetine (FXT), are effective for treatment of depressive disorders in most cases of schizophrenia. The effectiveness of SSRIs is not immediate; therefore, medication can take up to several weeks to be fully effective. FXT is one of the top ten prescribed antidepressants. FXT is prescribed in cases of depressive disorders in adults and adolescents [1], obsessive-compulsive and anxiety-depressive disorders [2], as well as for the therapy of bulimia nervosa [3]. Pharmacogenetic markers of FXT safety are being actively studied. Some pharmacogenetic markers of therapy safety have been established: genes of serotonin receptor isoforms and its transporters (HTR1A, HTR1B, SCL6A4).

ARTICLE 

84-92 200
Abstract

Diazepam is one of the most widely prescribed tranquilizers for the therapy of alcohol withdrawal syndrome (AWS). However, diazepam therapy often turns out to be ineffective, and some patients experience dose-dependent adverse drug reactions. Previous studies have shown that the metabolism of diazepam involves the CYP2C19 isoenzyme, whose activity is highly dependent on polymorphism of the encoding gene. The objective of our study was to investigate the effects of CYP2C19*2 genetic polymorphisms on plasma and saliva concentrations of diazepam as well as its impact on the efficacy and safety rates of therapy in patients with AWS. The study was conducted on 100 Russian male patients with AWS who received diazepam in injections at a dosage of 30.0 mg/day for 5 days. Genotyping was performed by real-time polymerase chain reaction. The efficacy and safety assessment was performed using psychometric scales. We revealed differences in the efficacy and safety of therapy in patients with different CYP2C19 681G>A genotypes. Therapeutic drug monitoring (TDM) revealed the statistically significant differences in the levels of diazepam plasma concentration: (GG) 199.83 [82.92; 250.58] vs (GA+AA) 313.47 [288.99; 468.33], p=0.040, and diazepam saliva concentration: (GG) 2.80 [0.73; 3.80] vs (GA+AA) 5.33 [5.14; 6.00], p=0.003).



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ISSN 2712-9179 (Online)