About 20% of patients with depression are diagnosed with alcohol dependence, and alcohol dependent individuals are at a higher risk of developing depression. A number of authors point to the relationship of CLOCK gene activity with both affective disorders and alcohol use/dependence disorders; in particular, variations in the CLOCK gene at the evidence level link to depression and stress.Objective: to establish clinical and genetic associations of the CLOCK circadian rhythm gene and depressive disorders during the period of abstinence in patients with alcohol dependence syndrome.Patients and methods. From June 2019 to December 2022, 402 patients (mean age 42.47±7.5 years) were examined, who underwent outpatient follow-up at a narcological dispensary not earlier than 1 month after and not later than 2 months after discharge from the hospital. All patients were diagnosed with middle-stage alcohol dependence syndrome, early remission phase. Depending on the presence of an episode of depression at the time of the examination, the main group (patients with a depressive disorder; n=128) and a comparison group (patients without a depressive disorder; n=274) were formed. Clinical interviews and psychometric study using the Montgomery–Asberg Depression Scale, were conducted for all the subjects. All subjects provided 10 ml venous blood samples for molecular, genetic and biochemical studies.Results and discussion. Correlations were found between the carriage of the TT genotype of the CLOCK gene in patients with alcohol dependence and concomitant clinical depression. Carrying the TT genotype of the CLOCK gene is presumably associated with the predominance of the following symptoms of depression, which demonstrated statistically significant differences: loss of appetite, impaired concentration, apathy, as well as with a higher overall score on the MADRS depression scale. The established association between the CLOCK gene and depression in people with alcohol dependence can be considered as a vulnerability factor in relation to the development of depression in patients with the underlying disease – alcohol dependence syndrome.Conclusion. The CLOCK gene is associated with the development of depression in patients suffering from alcohol dependence. Carriers of the TT genotype of the CLOCK gene (rs1801260) to a greater extent than carriers of other genotypes are characterized by the development of comorbid depression, as well as the predominance of such clinical symptoms as loss of appetite, impaired concentration, apathy, and a higher overall score on the MADRS depression scale.

BACKGROUND:Quarantine measures with self-isolation of varying duration have been significant psychosocial stressors in the context of the COVID-19 pandemic. The serotonin selective reuptake inhibitor fluvoxamine has been considered as a prophylaxis against depression in early COVID-19 patients, with additional benefits apparently arising from its antiviral activity. In this narrative review, we draw attention to the body of evidence showing efficacy of fluvoxamine in protecting against depressive disorders in COVID-19 patients, while also attenuating the severity of COVID-19 disease, with a notable reduction in the need for intubation and lower mortality. We consider this potential two-fold action of fluvoxamine in the light of its pharmacogenetic and pharmacological profiles.SUBJECTS AND METHODS:Full-text publications in English and Russian in Google Scholar, PubMed, NCBI, Web of Science, and E-Library databases were selected by keywords, solitary and in combination (fluvoxamine, COVID-19, depression, anxiety, antidepressants, adverse reactions) for the period from March 01, 2020 to June 06, 2022. We also analyzed the full-text publications in English and Russian language reporting adverse reactions caused by fluvoxamine use for the period from 2012 to 2022.RESULTS:The literature search yielded 10 papers reporting on the efficacy fluvoxamine in relieving depressive symptoms in COVID-19 patients, and 3 papers on its effect on medical outcome. The preponderance of data indicated a dual therapeutic action of fluvoxamine, and our further literature investigation was informative about drug-drug interactions and genetic factors moderating the antidepressant efficacy of fluvoxamine.CONCLUSIONS:Patients with COVID-19 seeking psychopharmacological treatment for depressive symptoms must be informed of the benefits and risks of fluvoxamine use. Several lines of findings indicate this agent to possess an additional antiviral action. However, optimal dosage regimens and the trade-off with drug-drug interactions remain unclear. Pharmacogenetic testing may assist in evidence-based optimization of fluvoxamine dosages in the context of COVID-19 infection with comorbid depression.

Background: Suicidal behaviour is the leading cause of mortality from external causes at all ages worldwide. More than a million people commit completed suicide each year. According to the World Health Organisation, 25-50% of suicide victims suffered from alcohol and other substance use disorders, 22% of all suicide deaths were attributable to alcohol use (WHO, 2014). Several papers have suggested potential associations of insomnia and increased suicide risk in patients with alcoholism. We hypothesise that mutations in melatonin receptor genes may be associated with suicide risk in patients with alcoholism.Methods. The Insomnia Severity Index (ISI) was used as a tool to assess the presence and severity of insomnia. The Columbia Suicide Severity Rating Scale (C-SSRS) was used as a method to examine suicidal behavior. Genotyping of MTNR1A (rs34532313), MTNR1B (rs10830963) genes was performed using real-time polymerase chain reaction (RT-PCR). A comparative genetic study of two groups of patients was carried out: the first group, patients with alcohol dependence syndrome (F10.2); the second group, patients with alcohol dependence syndrome (F10.2) and insomnia, which persisted 7-14 days after starting alcohol withdrawal therapy.Results. Suicidal thoughts and a history of auto-aggressive behaviour were more common in subjects with insomnia in the post-withdrawal period. Carriers of the TT genotype of the MTNR1A gene (rs34532313) were more likely to have suicidal thoughts and a history of suicide attempts in a genetic study of patients with insomnia.Conclusions. Our study found that the TT genotype of the MTNR1A gene (rs34532313) is a genetic marker of suicidal behaviour risk in patients with insomnia in the post-withdrawal period. However, the same pattern was not observed in patients without insomnia.

The antipsychotic-induced metabolic disorders (AIMD) are common side effects during the treatment of schizophrenia. Single nucleotide polymorphisms in the genes associated with AIMD, in particular in the leptin and neuropeptide Y genes were explored. The aim of this study was to develop a real-time PCR technique for SNP allele discrimination and allele frequency estimation in the Russian population. A total of 9 real-time PCR tests for rs7799039, rs1137101, rs8179183, rs16147, rs6837793, rs11100494, rs1414334, rs3813929 and rs518147 SNPs were developed and examined using 106 DNA samples. The revealed allele frequencies did not show any statistically significant differences with ones for the Caucasian population from Ensembl data base. Thus, our results are in accordance with the allele frequencies for the studied populations and allow using published data on the risk alleles for the development of new diagnostics PCR kits for the complex diagnostics of AIMD.

Background: The usage of antipsychotics (APs) is the most robust and scientifically based approach in the treatment of schizophrenia spectrum disorders (SSDs). The efficiency of APs is based on a range of target receptors of the central nervous system (CNS): serotoninergic, dopaminergic, adrenergic, histaminergic and cholinergic. Metabolic disorders are the most severe adverse drug reactions (ADRs) and lead to cardiovascular diseases with a high rate of mortality in patients with SSDs. Neuropeptide Y receptor Y5 (NPY5R) is known in the chain of interaction to target receptors for APs, agouti-related peptide receptors and proopiomelanocortin receptors. We studied the association of the single-nucleotide variants (SNVs) rs11100494 and rs6837793 of the NPY5R gene, and rs16147, rs5573, rs5574 of the NPY gene, with metabolic disorders in Russian patients with SSDs. Methods: We examined 99 patients with SSDs (mean age-24.56 years old). The mean duration of APs monotherapy was 8 weeks. The biochemical blood test included levels of glucose, cholesterol, lipoproteins, alanine aminotransferase (ALT), aspartate aminotransferase (AST), total protein and albumin. Anthropometry included weight, height, waist circumference and hip circumference. We used real-time PCR to study the carriage of major and minor alleles of the SNV rs11100494 (1164C>A) of the NPY5R gene (chromosome localization-4q32.2). Group 1 comprised 25 patients with SSDs taking APs with a change in body weight of more than 6% since the start of APs therapy. Group 2 comprised 74 patients with SSDs taking APs with a change in body weight of less than 6% since the start of APs therapy. Results: We show the significance of genetic risk factors (carriage of major allele C of SNV rs11100494 of the NPY5R gene) for the development of AP-induced weight gain in Russian patients with SSDs. The allele C predisposes to AP-induced weight gain (OR = 33.48 [95% CI: 12.62; 88.82], p-value < 0.001). Additionally, the results of our study demonstrate that first-generation APs (FGAs) are more likely to cause an increase in serum transaminase levels but are less likely to increase body weight. Second-generation APs (SGAs) are more likely to cause weight gain and changes in serum glucose levels. Conclusion: Our study shows the predictive role of the allele C of SNV rs11100494 of the NPY5R gene in the development of AP-induced weight gain. However, we did not find a significant association between biochemical markers and this SNV in Russian patients with SSDs.

Metabolic syndrome (MetS) is a clustering of at least three of the following five medical conditions: abdominal obesity, high blood pressure, high blood sugar, high serum triglycerides, and low serum high-density lipoprotein (HDL). Antipsychotic (AP)-induced MetS (AIMetS) is the most common adverse drug reaction (ADR) of psychiatric pharmacotherapy. Herein, we review the results of studies of blood (serum and plasma) and urinary biomarkers as predictors of AIMetS in patients with schizophrenia (Sch). We reviewed 1440 studies examining 38 blood and 19 urinary metabolic biomarkers, including urinary indicators involved in the development of AIMetS. Among the results, only positive associations were revealed. However, at present, it should be recognized that there is no consensus on the role of any particular urinary biomarker of AIMetS. Evaluation of urinary biomarkers of the development of MetS and AIMetS, as one of the most common concomitant pathological conditions in the treatment of patients with psychiatric disorders, may provide a key to the development of strategies for personalized prevention and treatment of the condition, which is considered a complication of AP therapy for Sch in clinical practice.

(1) Introduction: Extrapyramidal disorders form the so-called extrapyramidal syndrome (EPS), which is characterized by the occurrence of motor disorders as a result of damage to the basal ganglia and the subcortical-thalamic connections. Often, this syndrome develops while taking medications, in particular antipsychotics (APs). (2) Purpose: To review studies of candidate genes encoding dopamine receptors as genetic predictors of development of AP-induced parkinsonism (AIP) and AP-induced tardive dyskinesia (AITD) in patients with schizophrenia. (3) Materials and Methods: A search was carried out for publications of PubMed, Web of Science, Springer, and e-Library 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 were possibly missed. (4) Results: The review considers candidate genes encoding dopamine receptors involved in pharmacodynamics, including genes DRD1, DRD2, DRD3, and DRD4. We analyzed 18 genome-wide studies examining 37 genetic variations, including single nucleotide variants (SNVs)/polymorphisms of four candidate genes involved in the development of AIP and AITD in patients with schizophrenia. Among such a set of obtained results, only 14 positive associations were revealed: rs1799732 (141CIns/Del), rs1800497 (C/T), rs6275 (C/T), rs6275 (C/T) DRD2; rs167771 (G/A) DRD3 with AIP and rs4532 (A/G) DRD1, rs6277 (C/T), rs6275 (C/T), rs1800497 (C/T), rs1079597 (A/G), rs1799732 (141CIns/Del), rs1045280 (C/G) DRD2, rs6280 (C/T), rs905568 (C/G) DRD3 with AITD. However, at present, it should be recognized that there is no final or unique decision on the leading role of any particular SNVs/polymorphisms in the development of AIP and AITD. (5) Conclusion: Disclosure of genetic predictors of the development of AIP and AITD, as the most common neurological adverse drug reactions (ADRs) in the treatment of patients with psychiatric disorders, may provide a key to the development of a strategy for personalized prevention and treatment of the considered complication of AP therapy for schizophrenia in real clinical practice.

The majority of patients with alcohol dependence syndrome suffer from sleep disorders, particularly insomnia, associated with a number of critical clinical aspects, increased suicide risk, anxiety and depression. The authors of relevant publications indicate associations between polymorphic melatonin genes and melatonin metabolism and symptoms of sleep disorders. However, the literature review failed to reveal any studies on the role of genetic polymorphism of circadian rhythm regulators in sleep disorders in patients with alcohol dependence.Objective: to determine the associations of polymorphic variants of genes HTR2A, MTNR1A, MTNR1B, CLOCK, DRD2 with sleep disorders risk in alcohol dependence syndrome.Patients and methods. 307 patients with alcohol dependence syndrome were screened, including 61 women (21%) and 246 (79%) men (mean age – 41.92±7.9 years). The presence and severity of sleep disorders were assessed by the Insomnia Severity Index. In addition, 10 ml of venous blood sample was obtained from all participants. Genotyping of single nucleotide variants of HTR2A (rs6313), MTNR1A (rs34532313), MTNR1B (rs10830963), CLOCK (rs1801260), DRD2 (rs1800497) genes was performed using real-time polymerase chain reaction. Statistical analysis of the data was conducted using parametric and nonparametric methods.Results and discussion. The carriage of the *G allele of the polymorphic variant of the MTNR1B (rs10830963) gene, and its genotypes are associated with a greater risk of insomnia than the carriage of *С/*С genotype. The carriage of the *С allele of the polymorphic variant of the CLOCK (rs1801260) gene, as well as the *С/*Т genotype, are associated with the presence of sleep disorders. No associations between polymorphic variants of the HTR2A (rs6313), DRD2 (rs1800497) genes and insomnia risk were detected in patients with alcohol dependence syndrome.Conclusion. The found associations reveal prospects for future research on melatonin's role in the pathophysiology of sleep disorders in patients with alcohol dependence and pathogenetic therapy for insomnia.

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.

Antipsychotic drugs are a critical modality in managing of schizophrenia. Although medications can be highly effective, response varies and some patients derive considerably less benefit than others. Long-term use of antipsychotic drugs is associated with the development of adverse reactions. Te safety advantages of the atypical drugs havebeen questioned because of their propensity to induce weight gain and alter glucose and lipid metabolism. Antipsychotic-induced weight gain is a common cause of self-discontinuation of treatment and a significant deterioration in the quality of life in patients with schizophrenia. Te severity of adverse reactions when taking antipsychotics in different patients varies, which be associated with genetic factors. Antipsychotic induced weight gain is a major health concern and unfortunately, there is no predictive tool to identify who are high risk individuals. Te LEP, LEPR and NRY genes represents a compellings candidates for genetic studies of antipsychotic-induced weight gain. Candidate gene selection should rely on current knowledge on the molecular pathways to weight gain, antipsychotic pharmacokinetics and pharmacodynamics, as well as possible disease-related genetic links to the side effects under study. Pharmacogenetics will provide rational treatment based on matching antipsychotics to a patient’s DNA profile, thus, potentially providing effective treatment with minimal side effects to outliers and mean responders to a given antipsychotic medication.

Цель: Изучение роли носительства полиморфного варианта гена LEP (rs3828942) в развитии антипсихотикиндуцированных нарушении углеводного обмена у пациентов с шизофрениеи, постоянно проживающих в европеискои части Россиискои Федерации. Материалы и методы: В проспективное исследование были включены 117 взрослых пациентов с расстроиствами шизофренического спект ра (F2 по МКБ10) и без хронических соматических заболевании в стадии декомпенсации, постоянно проживающих в европеискои части Россиискои Федерации. Пациенты принимали антипсихотики в режиме монотерапии. Результаты: Носительство аллели А однонуклеотидного варианта Lys656Asn (rs3828942) гена лептина LEP ассоциировано с развитием нарушении углеводного обмена (увеличением концентрации глюкозы в плазме крови натощак до значения выше 6,1 ммоль/л) у пациентов с шизофрениеи, принимающих антипсихотики. Выводы: Полиморфность гена лептина LEP может являться фактором формирования нарушении углеводного обмена.

The article discusses the current state of the use of pharmacogenetic testing in clinical practice in the field of psychiatry, narcology and neurology in the Russian Federation. The active introduction of pharmacogenetic testing in clinical practice contributes to a personalized approach to predicting the pharmacological response to drugs, increasing the safety and effectiveness of pharmacotherapy, complience and the quality of life of patients with neuropsychiatric disorders. In the future, an increase in the availability of pharmacogenetic testing in real clinical practice is expected.

Objective : The effectiveness and safety of antidepressant therapy is a major problem. Only 25 % of patients with major depressive disorder (MDD) received adequate treatment, whereas only 20–30 % of patients whose symptoms were fully controlled by treatment relapsed. Trazodone is a triazolopyridine derivative can be used as monotherapy and as part of a combination strategy for addressing patients with treatment-resistant depression. Purpose : Systematization of data about the role of pharmacogenomics factors ontrazodone effectiveness and adverse trazodone reactions. Method : A literature search was conducted from Google Scholar, PubMed, Oxford academic, Scopus, PubChem, MedLine, Web of Science, e-LIBRARY and Pharm GKB databases from 1976 to 2018 using the combination of terms Trazodone AND Personalized Medicine OR SNP OR Pharmacogenetics. Results : 8 single-nucleotide polymorphisms (SNPs) cytochrome P450 (CYP2D6, CYP3A4, CYP1A2 and CYP3A5) and P-glycoprotein (ABCB1) genes were analyzed. Conclusions : The most promising markers of safety and efficacy of trazodone are SNP serotonin receptors genes, cytochrome P450 genes (CYP3A4 and CYP1A2) and ABCB1 gene. However, unambiguous results were obtained only for rs1045642 polymorphismsABCB1 gene and CYP3A5*3 СYP3A5 gene. Other genotype dSNPs not having any strong association with the therapeutic response. Future studies, including larger sample sizes, are needed.