Translating and adapting the Alcohol Use Disorders Identification Test (AUDIT) for use in the Russian Federation: A multicentre pilot study to inform validation procedures.

Aims: The Alcohol Use Disorders Identification Test (AUDIT) is one of the most widely used screening instruments worldwide. Although it was translated into many languages, not many country-specific adaptations exist, and a formal validation procedure of the Russian version has been carried out only recently. The present contribution documents the different steps taken to formally translate and adapt a Russian-specific version of the AUDIT (RUS-AUDIT). Methods: The AUDIT was translated into Russian following an established protocol, revised and adapted to the country context using an expert panel, and field-tested in an iterative approach, in line with WHO rules on instrument translation and adaptation A total of three pilot phases were carried out on 134 patients from primary healthcare (PHC) and 33 patients from specialised alcohol treatment facilities (narcology), guided by a specially established advisory board. Changes in each version were informed by the findings of the previous pilot phase and a thorough panel discussion. Results: Based on the findings of three different pilot phases, the RUS-AUDIT was developed as a paper-and-pencil interview for PHC professionals. Since various issues with representation and counting of standard drinks for the second test item arose, a special show card was developed to support the assessment. Preliminary AUDIT-C scores indicated that more than one-third of the screened women (34.2%) and about half of the screened men (50.9%) from PHC facilities have exceeded risk thresholds. Conclusions: The RUS-AUDIT was constructed as a feasible assessment tool for interviewers and patients. The large number of PHC patients who exceed the risk threshold has corroborated the need for formal validation and Russia-specific cut-off scores, considering the specific drinking patterns.

Investigating the Use of Pharmacogenetic and Pharmacometabolomic Markers to Predict Haloperidol Efficacy and Safety Rates.

Background: Haloperidol is commonly prescribed to patients with alcohol-induced psychotic disorder (AIPD). Notably however, individuals differ extensively with regards to therapeutic response and adverse drug reactions (ADRs). Previous studies have shown that haloperidol biotransformation is mainly metabolized by CYP2D6. Objective: The objective of our study was to investigate the use of pharmacogenetic (CYP2D6*4 genetic polymorphism) and pharmacometabolomic biomarkers to predict haloperidol efficacy and safety rates. Material and Methods: The study enrolled 150 patients with AIPD. Therapy included haloperidol in a daily dose of 5 to 10 mg/day by injections for 5 days. Efficacy and safety of treatment were evaluated using the validated psychometric scales PANSS, UKU, and SAS. Results: No association of the urinary 6-НО-ТНВС/pinoline ratio values which could be evidence of the CYP2D6 activity level with both the efficacy and safety rates of haloperidol was demonstrated. However, a statistically significant association between haloperidol safety profile and CYP2D6*4 genetic polymorphism was demonstrated (P < .001). Conclusion: To predict haloperidol efficacy and safety rates, utilization of pharmacogenetic testing that defines CYP2D6*4 genetic polymorphism is found preferable over the use of the pharmacometabolomic marker in a clinical setting.

Meta-analysis of pharmacogenetic clinical decision support systems for the treatment of major depressive disorder.

The study aimed to conduct a meta-analysis of studies comparing pharmacogenetically guided dosing of antidepressants with empiric standard of care. Publications referring to genotype-guided antidepressant therapy were identified via PubMed, Google Scholar, Scopus, Web of Science, Embase, and Cochrane databases from the inception of the databases to 2021. In addition, bibliographies of all articles were manually searched for additional references not identified in primary searches. Studies comparing clinical outcomes between two groups of patients who received antidepressant treatment were included in meta-analysis. Analysis of the data revealed statistically significant differences between the experimental group receiving pharmacogenetically guided dosing and the empirically treated controls. Specifically, genotype-guided treatment significantly improved response and remission of patients after both eight and twelve weeks of therapy, whereas no effect on the development of adverse drug reactions was observed. This meta-analysis indicates that the use of preemptive genotyping to guide dosing of antidepressants might increase treatment efficacy.

CYP3A4*22 and CYP3A5*3 impact efficacy and safety of diazepam in patients with alcohol withdrawal syndrome.

BACKGROUND: Diazepam is one of the most commonly prescribed pharmaceuticals for the treatment of alcohol withdrawal syndrome (AWS). However, diazepam sometimes is ineffective, and some patients experience dose-dependent adverse drug reactions (ADR). Previous studies have shown that diazepam metabolism involves the CYP3A4 and CYP3A5 isoenzymes, whose activity is highly variable between individuals, which may contribute to differences in clinical response. PURPOSE: The study aimed to investigate the effects of the genetic polymorphisms CYP3A4*22 and CYP3A5*3 on the efficacy and safety of diazepam in patients with AWS. MATERIALS AND METHODS: One hundred male AWS patients received 30 mg/day diazepam by intramuscular injections for 5 days. Genotyping for CYP3A4*22 (rs35599367) and CYP3A5*3 (rs776746) was performed by real-time polymerase chain reaction with allele-specific hybridization. The efficacy and safety assessments were performed using psychometric scales. RESULTS: Patients who carry CT and TT genotypes by polymorphic marker C > T intron 6 (rs35599367) of the CYP3A4 gene had a higher risk for ADR and demonstrated lower safety of diazepam therapy (p < 0.001; two-way ANOVA). CONCLUSION: These results suggest that genotyping for common CYP3A variants might have the potential to guide benzodiazepine withdrawal treatment.

Genetic testing is superior over endogenous pharmacometabolomic markers to predict safety of haloperidol in patients with alcohol-induced psychotic disorder.

BACKGROUND: Previous studies have shown that haloperidol biotransformation is mainly metabolized by CYP2D6. The CYP2D6 gene is highly polymorphic, contributing to inter-individual differences in enzymatic activity, and may impact haloperidol biotransformation rates, resulting in variable drug efficacy and safety profiles. OBJECTIVE: The study aimed to investigate the correlation of the CYPD6 activity with haloperidol's efficacy and safety rates in patients with alcohol-induced psychotic disorders. METHOD: One hundred male patients received 5-10 mg/day haloperidol by injections for 5 days. The efficacy and safety assessments were performed using PANSS, UKU, and SAS-validated psychometric scales. RESULTS: No relationship between haloperidol efficacy or safety and the experimental endogenous pharmacometabolomic marker for CYP2D6 activity, urinary 6-НО-ТНВС/pinoline ratio was identified. In contrast, we found a statistically significant association between haloperidol adverse events and the most common CYP2D6 loss-of-function allele CYP2D6*4 (p<0.001). CONCLUSION: Evaluation of the single polymorphism rs3892097 that defines CYP2D6*4 can predict the safety profile of haloperidol in patients with AIPD, whereas metabolic evaluation using an endogenous marker was not a suitable predictor. Furthermore, our results suggest haloperidol dose reductions could be considered in AIPD patients with at least one inactive CYP2D6 allele.

Effects of CYP2D6*4 polymorphism on the steady-state concentration of paroxetine in patients diagnosed with depressive episode and comorbid alcohol use disorder.

INTRODUCTION: Selective serotonin reuptake inhibitors have a common and increasing use for the treatment of patients diagnosed with depressive disorders. Some of them do not respond adequately to therapy, and numerous previous studies have indicated an increased risk of type A adverse drug reactions. OBJECTIVE: The objective of our study was to evaluate the effect of 1846G>A polymorphism of CYP2D6 on the concentration/dose ratio of paroxetine. MATERIAL AND METHODS: The study enrolled 267 patients with depressive episode (average age, 40.3 ± 14.3 years). Therapy included paroxetine in an average daily dose of 25.1 ± 9.5 mg per day. The efficacy and safety rates of treatment were evaluated using the international psychometric scales. For genotyping, we performed the real-time polymerase chain reaction. Therapeutic drug monitoring has been performed using high-performance liquid chromatography mass spectrometry (HPLC-MS/MS). RESULTS: Our study revealed the statistically significant results in terms of treatment efficacy (Hamilton Depression Rating Scale scores): (GG) 2.0 [1.0; 3.0] and (GA) 4.0 [2.0; 5.0], p < 0.001; meanwhile, no statistically significant results were obtained for the safety profile (Udvalg for Kliniske Undersogelser (UKU) Scale scores): (GG) 3.0 [2.0; 3.0] and (GA) 3.0 [3.0; 4.0], p = 0.056. We revealed the statistically significant results for the concentration/dose ratio of paroxetine in patients with different genotypes: (GG) 2.803 [2.154; 4.098] and (GA) 5.098 [3.560; 7.241], p < 0.001. CONCLUSION: The effect of CYP2D6*4 genetic polymorphism on the efficacy profile of paroxetine was demonstrated in a group of 267 patients with depressive disorder.

Effects of CYP2C19*17 genetic polymorphisms on plasma and saliva concentrations of diazepam in patients with alcohol withdrawal syndrome.

INTRODUCTION: Diazepam is one of the most commonly 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. OBJECTIVE: The study aimed to investigate the effects of CYP2C19*17 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. MATERIAL AND METHODS: The study was conducted on 100 Russian male patients suffering from the AWS who received diazepam injections at a dosage of 30.0 mg/day for 5 days. Genotyping was performed by real-time PCR with allele-specific hybridization. The efficacy and safety assessment was performed using psychometric scales. RESULTS: Based on the results of the study, we revealed differences in the efficacy and safety of therapy in patients with different CYP2C19 -806C>T genotypes. Therapeutic drug monitoring revealed the statistically significant difference in the levels of diazepam plasma concentration: (CC) 251.76 (214.43; 310.61) vs. (CT+TT) 89.74 (54.18; 179.13); P = 0.003, and diazepam saliva concentration: (CC) 3.86 (3.22; 5.12) vs. (CT+TT) 0.79 (0.44; 1.56); P = 0.003. CONCLUSION: Our study showed the effects of CYP2C19*17 genetic polymorphisms on the efficacy and safety rates of diazepam. Furthermore, we revealed the statistically significant differences in plasma and saliva concentration levels of diazepam in patients carrying different genotypes.

Using the CYP3A Activity Evaluation to Predict the Efficacy and Safety of Diazepam in Patients With Alcohol Withdrawal Syndrome.

BACKGROUND: Diazepam is one of the most commonly prescribed tranquilizers for the therapy of alcohol withdrawal syndrome (AWS). Despite its popularity, there is currently no precise information on the effect of genetic polymorphisms on the efficacy and safety of diazepam therapy. OBJECTIVE: The objective of our study was to study the effect of CYP3A isoenzymes activity on the efficacy and safety of diazepam in patients with AWS. METHODS: The study was conducted on 30 Russian male patients suffering from the AWS who received diazepam in injections at a dosage of 30.0 mg / day for 5 days. The efficacy and safety assessment was performed using psychometric scales and scales for assessing the severity of adverse drug reactions. RESULTS: Based on the results of the study, we revealed the differences in the efficacy of therapy in patients with different CYP3A4 C>T intron 6 (rs35599367) genotypes: (CC) -9.0 [-13.0; -5.0], (CT+TT) -13.5 [-15.0; -10.0], p = 0.014. The scores on the UKU scale, which was used to evaluate the safety of therapy, were also different: (CC) 7.5 [6.0; 11.0], (CT+TT) 11.0 [8.0; 12.0], p = 0.003. CONCLUSION: Possible relationship between the CYP3A activity, evaluated by the content of the urinary endogenous substrate of the given isoenzyme and its metabolite, the 6-beta-hydroxy cortisol (6-ß-HC) / cortisol ratio, and the efficacy of diazepam was demonstrated. This possible relationship was also supported by the genotyping results. This should be taken into consideration when prescribing this drug to such patients in order to reduce the risk of pharmacoresistance.

Effects of CYP2C19*17 Genetic Polymorphisms on the Steady-State Concentration of Diazepam in Patients With Alcohol Withdrawal Syndrome.

Background: Diazepam is one of the most widely prescribed tranquilizers for the therapy of alcohol withdrawal syndrome (AWS), which includes the symptoms of anxiety, fear, and emotional tension. However, diazepam therapy often turns out to be ineffective, and some patients experience dose-dependent adverse drug reactions, reducing the efficacy of therapy. Aim: The purpose of our study was to investigate the effects of CYP2C19*17 genetic polymorphisms on the steady-state concentration of diazepam in patients with AWS. Materials and Methods: The study was conducted on 50 Russian male patients suffering from the AWS. For the therapy of psychomotor agitation, anxiety, fear, and emotional tension, patients 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 and scales for assessing the severity of adverse drug reactions. Therapeutic drug monitoring (TDM) was performed using the high-performance liquid chromatography-mass spectrometry (HPLC-MS/MS) method. Results: Based on the results of the study, we revealed the differences in the efficacy of therapy in patients with different CYP2C19 -806C>T genotypes: (*1/*1) -12.0 [-15.0; -8.0], (*1/*17+*17/*17) -7.0 [-14.0; -5.0], P < .001, as well as the results of TDM: (CC) 250.70 [213.34; 308.53] ng/mL (*1/*17+*17/*17) 89.12 [53.26; 178.07] ng/mL, P < .001. Conclusion: Thus, our study enrolling 50 patients with AWS, showed the effects of CYP2C19*17 genetic polymorphisms on the efficacy and safety rates of diazepam. Furthermore, we revealed the statistically significant difference in the levels of plasma steady-state concentrations of diazepam in patients carrying different genotypes.

Impact of CYP2D6 Polymorphism on Equilibrium Concentration of Fluoxetine in Patients Diagnosed With Major Depressive Disorder and Comorbid Alcohol Use Disorders.

INTRODUCTION: Fluoxetine is used in the treatment of patients with recurrent depressive disorder. Some of these patients do not achieve an adequate response to a treatment regimen containing fluoxetine, and many of these patients experience dose-dependent adverse drug reactions. The cytochrome P450 enzyme CYP2D6 is involved in the biotransformation of fluoxetine, the activity of which is quite dependent on the polymorphism of the gene encoding this enzyme. OBJECTIVE: The objective of the study was to investigate the influence of the 1846G>A polymorphism of the CYP2D6 gene on the concentration/dose indicator of fluoxetine in patients diagnosed with major depressive disorder and comorbid alcohol use disorder. METHODS: Our study included 101 patients with major depressive disorder and alcohol use disorder (average age: 41.3±14.5 y) who were treated with fluoxetine at an average dose of 26.1±8.7 mg/d. Treatment efficacy was assessed using validated psychometric scales, and the safety/tolerability of the therapy was assessed using the Udvalg for Kliniske Undersogelser Side-Effect Rating Scale. Genotyping was done using a real-time polymerase chain reaction. Therapeutic drug monitoring was performed using high-performance liquid chromatography-mass spectrometry. RESULTS: CYP2D6 genotyping by polymorphic marker 1846G>A (rs3892097) in the 101 patients found that there were 81 patients (80.2%) with the GG genotype ("wild-type," normal metabolism), 20 (19.8%) with the GA genotype (intermediate metabolism), and no subjects with the AA genotype (poor metabolism). Statistically significant results in treatment efficacy as evaluated by Hamilton Rating Scale for Depression scores at the end of the treatment course were found: GG 9.0 [confidence interval (CI): 6.0; 12.0] and GA 12.0 (CI: 9.5; 14.0), P=0.005. Statistically significant results were also obtained for the safety profile as measured by scores on the Udvalg for Kliniske Undersogelser Side-Effect Rating Scale: GG 3.0 (CI 2.0; 4.0) and GA 5.0 (CI: 4.0; 5.0), P<0.001. Finally, a statistically significant difference was found in concentration/dose indicators of fluoxetine in patients with the different genotypes: GG 4.831 (CI: 3.654; 6.204) and GA 7.011 (CI: 5.431; 8.252), P<0.001. CONCLUSION: The effect of the genetic polymorphism of the CYP2D6 gene on the efficacy and safety profiles of fluoxetine was demonstrated in a group of 101 patients with major depressive disorder and alcohol use disorder.

The Association between the Alcohol Biomarker Phosphatidylethanol (PEth) and Self-Reported Alcohol Consumption among Russian and Norwegian Medical Patients.

AIMS: Valid measures to identify harmful alcohol use are important. Alcohol Use Disorders Identification Test (AUDIT) is a validated questionnaire used to self-report harmful drinking in several cultures and settings. Phosphatidylethanol 16:0/18:1 (PEth) is a direct alcohol biomarker measuring alcohol consumption levels. The aim of this study was to investigate how PEth levels correlate with AUDIT-QF and weekly grams of alcohol consumed among patients in two urban hospitals. In addition, we wanted to investigate the predictive value of PEth in identifying harmful alcohol use as defined by AUDIT-QF and weekly grams of alcohol cutoffs. METHODS: A cross-sectional study comprising acute medically ill patients with measurable PEth levels (≥0.030 µM) admitted to two urban hospitals in Oslo, Norway (N = 931) and Moscow, Russia (N = 953) was conducted using PEth concentrations in whole blood, sociodemographic data and AUDIT-QF questionnaires. RESULTS: PEth levels from patients with measurable PEth were found to be positively correlated with AUDIT-QF scores, with PEth cutpoints of 0.128 µM (Oslo) and 0.270 µM (Moscow) providing optimal discrimination for harmful alcohol use defined by AUDIT-QF (the difference between cities probably reflecting different national drinking patterns in QF). When converting AUDIT-QF into weekly grams of alcohol consumed, the predictive value of PEth improved, with optimal PEth cutpoints of 0.327 (Oslo) and 0.396 (Moscow) µM discriminating between harmful and non-harmful alcohol use as defined in grams (≥350 grams/week). CONCLUSIONS: By using PEth levels and converting AUDIT-QF into weekly grams of alcohol it was possible to get an improved rapid and sensitive determination of harmful alcohol use among hospitalized patients.

Using a pharmacogenetic clinical decision support system to improve psychopharmacotherapy dosing in patients with affective disorders.

OBJECTIVES: Although pharmacogenetic tests provide the information on a genotype and the predicted phenotype, these tests do not themselves provide the interpretation of data for a physician. Currently, there are approximately two dozen pharmacogenomic clinical decision support systems (CDSSs) used in psychiatry. Implementation of the CDSSs forming the recommendations on drug and dose selection according to the results of pharmacogenetic testing is an urgent task. Fulfillment of this task will allow increasing the efficacy of therapy and decreasing the risk of undesirable side effects. METHODS: The study included 118 male patients (48 in the main group and 70 in the control group) with affective disorders and comorbid alcohol use disorder. To evaluate the efficacy and safety of therapy, several international psychometric scales and rating scales to measure side effects were used. Genotyping was performed using the real-time polymerase chain reaction with allele-specific hybridization. Pharmacogenetic testing results were interpreted using free software PGX2 (LLE Medicine, Russian Federation, Biomedical Cluster of Skolkovo, Moscow Innovative Cluster; www.pgx2.com). RESULTS: The statistically significant differences across the scores on psychometric scales were revealed. For instance, the total score on the Hamilton Rating Scale for Depression by day 9 was 9.0 [8.0; 10.0] for the main group and 11.0 [10.0; 12.0] (p<0.001) for the control group and by day 16 it was 4.0 [2.0; 6.0] for the main group and 14.0 [13.0; 14.0] (p<0.001) for the control group. The UKU Side-Effect Rating Scale (UKU) also revealed a statistically significant difference. The total score on the UKU scale by day 9 was 4.0 [4.0; 5.0] for the main group and 5.0 [5.0; 6.0] (p<0.001) for the control group and by day 16 this difference grew significantly: 3.0 [0.0; 4.2] for the main group and 9.0 [7.0; 11.0] (p<0.001) for the control group. CONCLUSIONS: Pharmacogenetic-guided personalization of the drug dose in patients with affective disorders and comorbid alcohol use disorder can reduce the risk of undesirable side effects and pharmacoresistance. It allows recommending the use of pharmacogenetic CDSSs for optimizing drug dosage.

Prevalence of psychoactive substance use among acutely hospitalised patients in Oslo and Moscow: a cross-sectional, observational study.

OBJECTIVES: The use of psychoactive prescription medication is increasing in the general population. This is a cause for concern, particularly among the elderly, where physiological changes related to senescence increase the risk for adverse effects. While previous studies regarding psychoactive substance use have generally been population based, we sought to determine the frequency of such use among acutely hospitalised patients. SETTING: Two emergency departments (EDs), one in Oslo and one in Moscow, admitting patients to Departments of Internal Medicine. PARTICIPANTS: 5583 patients aged ≥18 years participated, distributed evenly between genders and study locations. Patients unable to give informed consent were excluded. The study sites did not admit patients with surgical conditions and/or injuries. PRIMARY AND SECONDARY OUTCOMES: The presence of psychoactive substances was determined through blood analysis using liquid chromatography-mass spectrometry. Secondary outcomes comprised demographic data (including age, gender, employment and marital status), degree of psychological distress, concurrent alcohol use, and self-reported alcohol, psychoactive drug and illicit substance use. RESULTS: 32.3% in Oslo and 12% in Moscow were positive for one or more psychoactive medicinal drugs (benzodiazepines, z-hypnotics, opioids or barbiturates). In Oslo, medicinal drug use was associated with being aged 61 to 70 years (OR 2.40, 95% CI 1.61 to 3.58) compared with 18 to 40 years, and psychological distress (OR 2.61, 95% CI 2.06 to 3.30). In Moscow, psychoactive medicinal drug use was also associated with psychological distress (OR 1.68, 95% CI 1.18 to 2.39), and was less common among patients aged 41 to 60 years (OR 0.62, 95% CI 0.43 to 0.88) than among patients aged 18 to 40 years. CONCLUSION: A significant proportion of admitted patients used one or more psychoactive medicinal drugs, in particular benzodiazepines (Oslo and Moscow) and opiates (Oslo). We suggest formalised screening for inappropriate prescription drug use and increased adherence to clinical prescription guidelines.

Predictors of tobacco smoking among acutely ill patients in a Moscow hospital: A cross-sectional study.

INTRODUCTION: Tobacco smoking is a major preventable risk factor for non-communicable diseases. The aim of this study was to investigate predictors of tobacco smoking among acute medically ill patients admitted to a Moscow hospital, and the association between smoking and alcohol use. METHODS: Patients admitted to the V. P. Demikhov hospital in Moscow from November 2016 through December 2017 were asked to participate in this study (inclusion criteria were acute medically ill patients aged ≥18 years). Sociodemographic data were collected, in addition to questionnaires on mental distress (Hopkins Symptom Checklist 5), alcohol use (Alcohol Use Disorder Identification Test 4, AUDIT-4) and smoking (Fagerström Test for Nicotine Dependence). RESULTS: A total of 3009 patients were recruited to the study. Using a binary logistic regression model adjusted for all variables, it was found that living without a partner resulted in a higher risk of smoking tobacco compared to being married or living with a partner (odds ratio, OR=1.60 for divorced, p=0.001; and OR=1.62 for single, p=0.002), and being economically non-active resulted in a higher risk compared to being economically active (OR=1.47; p=0.003). Harmful alcohol use (AUDIT-4 score ≥5 [for females] / 7 [for males]) resulted in a higher risk of smoking compared to those without harmful alcohol use (OR=4.04; p<0.001). CONCLUSIONS: Smoking was highly prevalent and associated with other adverse sociodemographic and lifestyle factors such as harmful alcohol use.

CYP3A subfamily activity affects the equilibrium concentration of Phenazepam® in patients with anxiety disorders and comorbid alcohol use disorder.

Phenazepam® is prescribed to relieve anxiety and sleep disorders during alcohol withdrawal, although it is associated with undesirable side effects. Aim: To demonstrate changes in the safety and efficacy profiles of Phenazepam in patients with anxiety disorders and comorbid alcohol use disorder. Materials & methods: A total of 94 Russian patients with alcohol use disorder received 4.0 mg of Phenazepam per day in tablets. We used a urinary 6-beta-hydroxycortisol/cortisol ratio to evaluate CYP3A activity. Results: A statistically significant inverse correlation between Phenazepam plasma concentration and CYP3A activity was found (r = -0.340 and p = 0.017). Correlation between the concentration/dose ratio and phenotyping results was also statistically significant (r = 0.301 and p = 0.026). Conclusion: The safety and efficacy of Phenazepam depend on CYP3A genetic polymorphisms.

How do CYP2C19*2 and CYP2C19*17 genetic polymorphisms affect the efficacy and safety of diazepam in patients with alcohol withdrawal syndrome?

Background Diazepam is one of the most commonly prescribed tranquilizers for therapy of alcohol withdrawal syndrome (AWS). Despite its popularity, there is currently no precise information on the effect of genetic polymorphisms on its efficacy and safety. The objective of our study was to investigate the effect of CYP2C19*2 and CYP2C19*17 genetic polymorphisms on the efficacy and safety of diazepam in patients with AWS. Methods The study was conducted on 30 Russian male patients suffering from the AWS who received diazepam in injections at a dosage of 30.0 mg/day for 5 days. The efficacy and safety assessment was performed using psychometric scales and scales for assessing the severity of adverse drug reactions. Results Based on the results of the study, we revealed the differences in the efficacy of therapy in patients with different CYP2C19 681G>A (CYP2C19*2, rs4244285) genotypes: (CYP2C19*1/*1) -8.5 [-15.0; -5.0], (CYP2C19*1/*2 and CYP2C19*2/*2) -12.0 [-13.0; -9.0], p = 0.021. The UKU scale scores, which were used to evaluate the safety of therapy, were also different: (CYP2C19*1/*1) 7.0 [6.0; 12.0], (CYP2C19*1/*2 and CYP2C19*2/*2) 9.5 [8.0; 11.0], p = 0.009. Patients carrying different CYP2C19 -806C>T (CYP2C19*17, rs12248560) genotypes also demonstrated differences in therapy efficacy and safety rates. Conclusions Thus, the effects of CYP2C19*2 and CYP2C19*17 genetic polymorphisms on the efficacy of diazepam were demonstrated.

Effects of CYP2C19*17 polymorphisms on the efficacy and safety of bromodigyrochlorophenylbenzodiazepine in patients with anxiety disorder and comorbid alcohol use disorder.

Background Bromodihydrochlorophenylbenzodiazepine (Phenazepam®) is used in the therapy of anxiety disorders in patients with alcohol dependence. However, Phenazepam therapy often turns out to be ineffective, and some patients develop dose-related adverse drug reactions (ADR): severe sedation, dizziness, headache, dyspepsia, falling, etc. That ensures the effectiveness of this category of patients. Despite the popularity of Phenazepam® as an anxiolytic drug, there is currently no accurate data on its biotransformation, as well as the effect of polymorphism of a gene on the efficacy and safety of bromodihydrochlorophenylbenzodiazepine in patients. The aim of our study was to study the effect of the polymorphism of the CYP2C19 gene on the efficacy and safety index of Phenazepam® for patients with anxiety disorders, using algorithms for optimizing the therapy of Phenazepam® to reduce the risk of pharmacological resistance and increase the effectiveness of therapy. Methods The study was conducted on 86 Russian patients suffering from alcohol dependence. Patients with trauma anxiety disorders received bromdihydrochlorphenylbenzodiazepine in tablets at a dose of 4.0 [2.0; 6.0] mg per day for 5 days. Genotyping was carried out by the method of polymer chain reaction in real time with allele-specific hybridization. Efficiency and safety assessment was carried out using psychometric scales and scales of Hospital Anxiety and Depression Scale (HADS) severity scores. Results Based on the results of the study, statistically significant differences in the number of scores on the scale of HADS severity of CYP2C19 CT on the third day of therapy were the following: (CC) 10.00 [9.00; 11.00], (CT) 14.00 [13.00; 16.00], (TT) 18.00 [17.00; 19.00], p=0.00, and also on the fifth day: (CC) 6.00 [5.00; 7.00], (CT) 17.50 [16.25; 19.75], (TT) 22.50 [20.00; 24.00], p=0.00. ADRs in patients with different genotypes for this polymorphic marker did not differ. Conclusions Thus, it has been shown that the polymorphism of the CYP2C19 gene may influence the effectiveness indices of Phenazepam therapy in patients with anxiety disorders comorbid with alcohol dependence. This should be taken into account in the appointment of this drug in this way in order to increase effectiveness of therapy and improve the quality of life.

Using a personalized clinical decision support system for bromdihydrochlorphenylbenzodiazepine dosing in patients with anxiety disorders based on the pharmacogenomic markers.

INTRODUCTION: Although pharmacogenetic tests provide the information on a genotype and the predicted phenotype, these tests themselves do not provide the interpretation of data for a physician. There are currently approximately two dozen pharmacogenomic clinical decision support systems used in psychiatry. Implementation of clinical decision support systems capable of forming recommendations on drug and dose selection according to the results of pharmacogenetic testing is an urgent task. Fulfillment of this task may allow increasing the efficacy of therapy and decreasing the risk of undesirable side effects. MATERIALS AND METHODS: The study included 51 male patients (21 in the main group and 30 in the control group) with alcohol withdrawal syndrome. To evaluate the efficacy and safety of therapy, several international psychometric scales and rating scales to measure side effects were used. Genotyping was performed using real-time polymerase chain reaction with allele-specific hybridization. Pharmacogenetic test results were interpreted using free software PGX2 (www.pgx2.com). RESULTS: Statistically significant differences between the scores derived from all psychometric scales were revealed. For instance, the total score on CIWA-Ar scale by day 3 was 13.5 [11.2; 16.0] for the main group and 18.0 [17.0; 22.0] (p < 0.001) for the control group; by day 5, it was 6.5 [4.2; 8.0] for the main group and 15.0 [14.0; 16.0] (p < 0.001) for the control group. The UKU side effect rating scale (UKU) also revealed a statistically significant difference. The total score on UKU scale by day 3 was 6.0 [5.0; 7.0] for the main group and 7.0 [6.0; 8.0] (p < 0.001) for the control group; by day 5, this difference grew significantly: 5.5 [3.0; 9.0] for the main group and 14.0 [12.0; 19.0] (p < 0.001) for the control group. The groups were representative (there was no difference between the scores at the inclusion of patients). CONCLUSION: Pharmacogenetic-guided personalization of drug dose in patients with alcohol withdrawal syndrome can reduce the risk of undesirable side effects and pharmacoresistance. It allows recommending the use of pharmacogenomic clinical decision support systems for optimizing drug dosage.

Effects of CYP2D6 genetic polymorphisms on the efficacy and safety of fluvoxamine in patients with depressive disorder and comorbid alcohol use disorder.

BACKGROUND: Fluvoxamine therapy is used for treatment of patients with depressive disorder, but it is often ineffective, and some patients suffer from dose-dependent undesirable side effects such as vertigo, headache, indigestion, xerostomia, increased anxiety, etc. CYP2D6 is involved in the biotransformation of fluvoxamine. Meanwhile, the genes encoding these isoenzymes have a high level of polymorphism, which may affect the protein synthesis. OBJECTIVE: The primary objective of our study was to investigate the effects of CYP2D6 genetic polymorphisms on the efficacy and safety of fluvoxamine in patients with depressive disorder and comorbid alcohol use disorder, in order to develop the algorithms of optimization of fluvoxamine therapy for reducing the risk of dose-dependent undesirable side effects and pharmacoresistance. METHODS: The study involved 45 male patients (average age: 36.44±9.96 years) with depressive disorder and comorbid alcohol use disorder. A series of psychometric scales was used in the research. Genotyping of CYP2D6 (1846G>A) was performed using real-time polymerase chain reaction. RESULTS: According to results of Mann-Whitney U-test, statistically significant differences between the efficacy and safety of fluvoxamine were obtained on 9th and 16th days of therapy in patients with GG and GA genotypes (The Hamilton Rating Scale for Depression: 10.0 [10.0; 23.0] vs 25.0 [24.0; 16.0] (P<0.001) on the 9th day and 4.0 [2.0; 5.0] vs 6.0 [6.0; 7.0] on the 16th day; The UKU Side Effect Rating Scale: 6.0 [4.0; 6.0] vs 9.0 [9.0; 10.0] (P<0.001) on the 9th day and 5.0 [1.0; 9.0] vs 19.0 [18.0; 22.0] on the 16th day). CONCLUSION: This study demonstrated the lower efficacy and safety of fluvoxamine in patients with depressive disorder and comorbid alcohol use disorders with GA genotype in CYP2D6 1846G>A polymorphic marker.

The influence of CYP3A5 polymorphisms on haloperidol treatment in patients with alcohol addiction.

BACKGROUND: Isoenzymes CYP2D6 and CYP3A4, the activity of which varies widely, are involved in metabolism of haloperidol and may influence its profile of efficacy and safety. OBJECTIVE: The primary aim of this study was to estimate the relationship between CYP3A5 gene polymorphism, activity of the CYP3A isoenzyme, and the risk of development of adverse drug reactions by haloperidol in patients with alcohol abuse. METHODS: Sixty-six male alcohol-addicted patients participated in the study. The safety of haloperidol was evaluated by Udvalg for Kliniske Undersogelser Side Effect Rating Scale (UKU) and Simpson-Angus Scale for extrapyramidal symptoms (SAS). The activity of CYP3A was evaluated by determining the concentrations of an endogenous substrate of this isoenzyme (cortisol) and its urinary metabolite (6-beta-hydroxycortisol, 6-B-HC). Genotyping of CYP3A5*3 was performed by real-time polymerase chain reaction with allele-specific hybridization. RESULTS: The frequency of A-allele occurrence in Russian population was very poor (2.27%). CYP3A5*3 polymorphism had no influence on safety profile indicators of haloperidol (UKU scale: p=0.55, SAS scale: p=0.64). In addition, there was no statistical significant difference between the values of indexes of the metabolic ratio (6-B-HC/cortisol) in groups with different genotypes of CYP3A5*3: GG 5.00 (3.36; 6.39) vs AG 5.26 (2.10; 6.78) (p=0.902). CONCLUSION: The frequency of A-allele occurrence of CYP3A5*3 in Russian population is very poor, and it has no high influence on the safety of haloperidol treatment; therefore, there are no reasons to take this polymorphism into account in patients with alcohol addiction who receive haloperidol.