Editor-in-Chief of Safety and Risk of Pharmacotherapy Renad N. Alyautdin presents an analysis of the article “­Sterol pathway disruption in pregnancy: A link to autism” (2026), published in Molecular Psychiatry, which reports the results of a large-scale retrospective RWD/RWE study of more than 6 million mother–child pairs (2014–2023). The study identifies an association between prenatal exposure to inhibitors of post-lanosterol cholesterol synthesis and the risk of autism spectrum disorder in children.

INTRODUCTION. Expanding prescription of anxiolytics due to high global incidence of anxiety disorders necessitates a safety assessment of these drugs in clinical practice.

AIM. This study aimed to assess the risks of adverse drug reactions (ADR) to the anxiolytics prescribed for neurotic disorders in the Russian Federation and to identify drugs with the most favorable safety profile.

MATERIALS AND METHODS. Spontaneous reports were submitted to Roszdravnadzor Automated Information System database over 2019–2024 (n=1,024) for drugs with the following international non-proprietary names: diazepam, tofisopam, bromdihydrochlorphenylbenzodiazepine, alprazolam, lorazepam, etifoxine, buspirone, and fabomotizole. The reporting odds ratio (ROR) and the proportionality ratio of reporting (PRR) were calculated for each international non-proprietary name regarding the most frequently reported ADR system organ classes (SOC).

RESULTS. Fatal ADRs were significantly associated with diazepam administration (ROR 10.98, [4.81, 25.05], p<0.001; PRR 48.56, p<0.001). A statistically significant ADR-drug association was established for: 1) diazepam and ADRs related to SOC Immune system disorders; General disorders and administration site conditions; Respiratory, thoracic and mediastinal disorders; and Vascular disorders; 2) bromdihydrochlorphenylbenzodiazepine and ADRs related to SOC Nervous system disorders and Psychiatric disorders; 3) tofisopam and ADRs related to SOC Gastrointestinal disorders. The risk of poisoning, overdoses, as well as suicide or intentional poisoning for benzodiazepine anxiolytics was comparable to non-benzodiazepine drugs (OR for poisoning/overdose 1.41 [0.46, 4.29], p=0.27; OR for suicide/intentional poisoning 1.75, [0.79, 3.9], p=0.08).

CONCLUSIONS. Hydroxyzine has been deemed the safest non-benzodiazepine anxiolytic, with diazepam being the least safe. Due to the low number of reports, further monitoring of ADR risks is warranted.

INTRODUCTION. The widespread use of antipsychotics (APs) makes the issue of antipsychotic-induced neurological adverse drug reactions clinically significant, as these reactions can limit the effectiveness of therapy for schi­zophrenia spectrum disorders and impair patients’ quality of life.

AIM. To critically evaluate current evidence on the frequency, underlying hypotheses, and strategies for the prevention and management of antipsychotic-induced neurological adverse drug reactions to optimize the treatment of schizophrenia spectrum disorders.

DISCUSSION. A review of the scientific literature was conducted using the PubMed, eLIBRARY.RU, Google Scholar, Cochrane Library, and Lens.org databases for the period 2020–2025. The frequency of neurological adverse drug reactions was found to vary among patients taking first-generation (AP1s), second-generation (AP2s), and third-generation (AP3s) antipsychotics. AP1s are characterized by a high incidence of acute extrapyramidal symptoms, including akathisia (14–35%), parkinsonism (18.5–51.3%), acute dystonia (1.4–60%), and hyperprolactinemia (40–70%). A key advantage of AP2s and AP3s is a significantly reduced risk of extrapyramidal syndrome, although the frequency of tardive dyskinesia and acute akathisia remains comparable to that observed with AP1s. Due to their affinity for cholinergic receptors, AP2s and AP3s may exert a greater negative impact on higher cortical functions compared to AP1s, potentially contributing to cognitive impairment.

CONCLUSIONS. Research from the last decade indicates a trend toward a changing profile of antipsychotic-induced neurological adverse reactions, coinciding with the increasingly widespread use of AP2s and AP3s in clinical psychiatry. A personalized approach to the choice of AP and its dose, including assessment of anticholinergic burden, therapeutic drug monitoring, and pharmacogenetic testing, can help achieve an optimal balance between the effectiveness and safety of psychopharmacotherapy.

INTRODUCTION. The safety of pharmacotherapy in patients with mental disorders is critical for accurate assessing systemic inflammatory processes. Psychopharmacotherapy may modulate the immune response, potentially masking systemic inflammatory response (SIR) signs in patients with psychosomatic disorders. This phenomenon complicates the differential diagnostic process and the selection of an appropriate treatment strategy.

AIM. To evaluate the effect of pre-admission psychotropic medication use on key markers of systemic inflammatory response (body temperature, leukocytosis, and C-reactive protein (CRP) levels) to enhance the safety of psychotropic pharmacotherapy and optimize therapeutic strategies in hospitalized patients with mental disorders.

MATERIALS AND METHODS. This single-center retrospective study analyzed data from 850 patients hospitalized between January 2024 and March 2025 with suspected infectious complications or decompensation of somatic pathology. Five classes of psychopharmacotherapeutic agents were evaluated: antipsychotics (n=270), antidepressants (n=56), antiepileptics (n=94), anxiolytics (n=15), and antiparkinsonian agents (n=63). Associations with febrile response (<37°C, ≤38°C, >38°C), leukocytosis, and elevated CRP levels were assessed using the Pearson χ² test, Fisher exact test, and the linear-by-linear association test.

RESULTS. No single drug class affected all three markers simultaneously. Antidepressant use was associated with a significant linear trend toward reduced fever severity (p=0.024). Antiepileptic use was associated with a lower incidence of leukocytosis (p=0.039). Polytherapy (use of ≥3 medications) was significantly associated with alterations in leukocyte counts (p=0.008) and CRP levels (p=0.006). Among individual agents, chlorprothixene and chlorpromazine were associated with higher, while risperidone was associated with lower, SIR parameter values. CRP levels remained consistently elevated and were not influenced by psychotropic medication use.

CONCLUSIONS. Pre-admission psychopharmacotherapy does not uniformly affect all SIR markers. Its effects are selective and most pronounced in the context of polytherapy. C-reactive protein confirmed its status as the most reliable inflammatory marker in this clinical setting. The identified associations support the importance of a personalized approach to treatment selection.

INTRODUCTION. The activity of cytochrome P450 enzymes (CYP450), which play a key role in antipsychotic metabolism, influences treatment efficacy and safety. Individualized drug selection and dosage using pharmacogenetic testing is crucial for treatment safety.

AIM. This review aimed to systematize data on the effects of polymorphisms of the CYP2D6, CYP2C19, CYP1A2, and CYP3A4 genes encoding CYP450 enzymes on antipsychotic plasma concentrations and the risk of adverse drug reactions, for integration into personalized treatment algorithms.

DISCUSSION. Key factors determining the efficacy and safety of antipsychotic therapy are differences in metabolism caused by polymorphisms in CYP450 isoenzyme genes: CYP2D6, CYP2C19, and CYP1A2. Patient genotype determines the metabolic phenotype. Based on the level of CYP450 activity, four major metabolizer phenotypes are distinguished: poor, intermediate, normal (most common), and ultrarapid metabolizers. The extreme metabolizer phenotypes have the most significant impact on antipsychotic prescribing strategies, particularly for second- and third-generation antipsychotics. Genotypes that determine metabolic rate are also associated with sex and ethnicity.

CONCLUSIONS. Integrating pharmacogenetic testing (primarily CYP2D6 genotyping) into clinical practice enables optimization of antipsychotic selection and dosing, enhances the efficacy and safety of schizophrenia treatment, and reduces healthcare costs. Testing is recommended for patients with an inadequate treatment response, those who develop adverse drug reactions, and when clozapine or olanzapine therapy is planned (CYP1A2).

INTRODUCTION. Continuous assessment of the dynamics of quantitative indicators and the impact of extraordinary events on them, such as the COVID-19 pandemic, is critically important for the development of the international drug safety monitoring program and national pharmacovigilance systems.

AIM. This study aimed to provide a preliminary assessment of the dynamics of quantitative indicators in the World Health Organization (WHO) VigiBase database in the periods before, during and after the COVID-19 pandemic (2017–2025) to identify trends for the expected identification of trends potentially related to changes in the global pharmacovigilance system under extraordinary events.

MATERIALS AND METHODS. The dynamics of the integral indicator of global pharmacovigilance, the annual total number of Individual Case Safety Reports (ICSR, cases) included in the VigiBase database in 2017–2025, divided into 3 periods of 3 years each: before the COVID-19 pandemic, during the pandemic and after the pandemic, was assessed. The data were analyzed using the VigiMatch statistical tool built into VigiLyze.

RESULTS. The development of global pharmacovigilance system in the period before the COVID-19 pandemic was reflected in an annual increase of 300–400 thousand cases. In 2021, there was a sharp increase in the number of cases, and the proportion of reports for COVID-19 vaccines out of the total number of cases during the pandemic was 39.2%. In the post-COVID period, the number of cases in the global pharmacovigilance system was below the predicted values. Deviations of the actual number of cases included annually in the global pharmaco vigilance system from the expected in 2020–2025, as well as changes in the ranking of data, occurred mainly due to active safety monitoring of the COVID-19 vaccines.

CONCLUSIONS. The identified trends in the global pharmacovigilance system in 2020–2025 may be preliminarily associated not only to the impact of the COVID-19 pandemic, but also to other causes and require further study.

INTRODUCTION. Many aspects of the drug safety profile, including rare and delayed adverse drug reactions (ADRs), are identified only in the post-marketing period when the drug is used in real-world clinical practice. However, the drawbacks inherent in spontaneous reporting and scientific literature monitoring (the main methods of post-marketing pharmacovigilance), such as incompleteness, fragmentation, variability in data quality, and the lack of standardized approaches to their analysis necessitate the systematization of information and the unification of approaches to data processing.

AIM. To systematize information on the spontaneous reporting method and scientific literature monitoring, as well as on data processing approaches in post-marketing pharmacovigilance for risk management and ensuring drug safety.

DISCUSSION. Spontaneous reporting is the basic passive method for post-marketing drug safety monitoring, with advantages including broad population coverage and the ability to detect a wide range of ADRs, including rare, delayed, and previously unknown ones. The effectiveness of the spontaneous reporting method can be enhanced through the development of educational programs for healthcare professionals and patients, the implementation of natural language processing (NLP) technologies to automate the extraction of structured information about ADRs from unstructured text sources, and integration with real-world data (RWD) to confirm signals and quantify risks. Scientific literature monitoring serves as a bridge between the passive collection of real-world data and evidence-based findings from controlled studies. An analysis of the EAEU Good Pharmacovigilance Practice Guidelines shows that when searching for information in the scientific literature, special aspects of the drug safety profile must be taken into account: effects on pregnancy outcomes, use in pediatrics, lack of efficacy, overdose, off-label use, and preclinical data. To standardize statistical methods for signal detection and the correct interpretation of signals (disproportionality analysis in spontaneous reporting databases), the READUS-PV guideline (2024) is recommended.

CONCLUSIONS. The modern methodology of post-marketing pharmacovigilance is a dynamically evolving system. The presented systematization of approaches to spontaneous reporting and scientific literature monitoring, as well as the list of mandatory drug safety aspects, can serve as a practical tool for specialists in planning and conducting drug safety assessments.

INTRODUCTION. Spontaneous reporting is a principal tool for obtaining information on adverse drug reactions (ADRs). However, incomplete entry of key fields in ADR report forms by reporters complicates causality assessment. The adequacy of available information for an objective causality assessment and pharmacovigilance decision-making, especially for drugs taken long-term, remains debatable. Osteoporosis was chosen as an example of a disease requiring long-term therapy, which increases the risks of adverse drug reactions and reduces treatment adherence.

AIM. This study aimed to evaluate the completeness of key fields in ADR report forms for drugs used in the treatment of osteoporosis within the Russian pharmacovigilance system and to determine the impact of missing information on the ability to perform causality assessment and assess treatment safety.

MATERIALS AND METHODS. A total of 1,802 spontaneous ADR reports for osteoporosis drugs were analyzed. The reports were registered in the Pharmacovigilance database of Roszdravnadzor’s Automated Information (the AIS Roszdravnadzor), versions 1.0 (2009–2019) and 2.0 (2019–2024). The proportion of missing data in each field was calculated.

RESULTS. Field completion varied widely. In version 1.0, missing data ranged from 1.15% (Anatomical Therapeutic Chemical classification code) to 74.0% (ADR resolution date); in version 2.0, from 2.4% (sex) to 65.9% (ADR resolution date). In both versions, basic patient characteristics (sex, age) were consistently reported, whereas start/end dates of pharmacotherapy, outcomes, and manufacturer were frequently missing. Compared with version 1.0, version 2.0 showed improved completion of clinical ADR fields but more missing data in “Manufacturer” and “Batch number”. The transition to version 2.0 produced mixed effects: fewer mandatory fields expanded reporting of ADR characteristics but reduced details needed for causality assessment.

CONCLUSIONS. The analysis of spontaneous reports revealed systematic gaps in ADR report forms for osteoporosis pharmacotherapy, hindering causality assessment. To improve pharmacovigilance and risk management, especially in patients with chronic diseases, standardization of data collection protocols is required, including mandatory completion of critical fields (ADR onset/resolution dates, concomitant therapy, actions taken, dechallenge/rechallenge outcomes) and targeted reporter education.

INTRODUCTION. Contamination of injection and infusion preparations in the vials with fragments of a punctured stopper (coring) poses direct risks of microembolism, inflammatory reactions in patients, and dosing errors. No risk minimization strategy for coring of a punctured stopper currently exists in the Russian Federation.

AIM. This study aimed to determine the ways to minimize contamination risk of an injectable drug with particles of a vial stopper punctured by a needle.

DISCUSSION. Standardized puncturing technique for vial stoppers was found to be a fundamental preventative measure: puncturing at an angle of 45–60º, followed by a right angle, with the bevel facing upwards, significantly reduces the risk of a fragmented stopper. Using small-gauge needles (≥20G) and restricting the number of punctures (as few as possible and at least 0.75 mm apart) also minimized coring. Filter needles that trap the resulting particles were substantiated as a reliable technological solution, as well as choosing closed-loop transfer systems and prefilled single-use syringes that prevents any stopper manipulations. The important elements of the strategy include a thorough visual inspection of each dose against a dark background under intense light and training medical personnel to puncture the vials using simulation techniques.

CONCLUSIONS. Based on the references, the strategy offered to minimize the risks associated with the vial stopper fragmentation at injection and infusion integrates technological, methodological, and organizational solutions. For practical implementation, it is recommended to standardize the puncturing technique of the vial stopper; to train medical personnel in puncturing techniques that reduce the risk of forming stopper particles; to visually inspect each dose of the drug before administration; and to use specific medical devices that prevent manipulations with the vial stopper.

INTRODUCTION. Herpesvirus infections are among the most common viral diseases in humans and have been classified by the WHO Regional Office for Europe as a group of diseases that determine the future of infectious pathology. Currently, the Russian Federation and the Eurasian Economic Union (EAEU) lack documents providing recommendations on conducting clinical trials of drugs for the treatment of herpes labialis that would establish the required scope of data for the registration of new products. Therefore, it is pertinent to analyze global regulatory practices, including the approaches of leading agencies such as the US Food and Drug Administration (FDA).

AIM. This study aimed to assess the feasibility of using and adapting the FDA methodological approach when developing a Russian guidance on planning a clinical trial program for new drugs for the treatment of herpes labialis.

DISCUSSION. A review of regulatory and methodological documents revealed that currently only one specialized guidance exists on conducting clinical trials of new drugs for the treatment of herpes labialis, prepared by the FDA (FDA Guidance). The FDA Guidance defines the specific features of conducting clinical pharmacology studies and confirmatory clinical trials (selection of the study population, design and duration of clinical trials, selection of primary and secondary efficacy endpoints, and safety assessment), as well as the specific features of conducting confirmatory clinical trials in children. A comparison with the regulatory documents of the Russian Federation and the EAEU showed that the methodological solutions presented in the FDA Guidance do not contradict the general principles of clinical trial conduct established in the current documents.

CONCLUSIONS. The provisions of the FDA Guidance meet all the requirements necessary for planning a clinical trial program and can serve as a basis for the guidance being developed for conducting clinical trials in the Russian Federation and the EAEU member states, taking into account regional specifics.

INTRODUCTION. Arterial hypertension remains one of the leading causes of cardiovascular morbidity and mortality, however, data on the effect of genetic polymorphisms on the efficacy and safety of angiotensin-converting enzyme (ACE) inhibitors are contradictory and fragmentary. The effectiveness of antihypertensive therapy may also decrease with smoking, overweight, excessive salt intake, and type 2 diabetes mellitus (T2DM). A comprehensive assessment of the effect of ACE gene polymorphisms and confounders will allow correct interpretation of the causes of variability in the effectiveness of ACE inhibitors and optimization of therapy.

AIM. This study aimed to evaluate the effect of the ACE gene D allele (I/D rs1799752) and concomitant confounders (age, sex, smoking, overweight, excess salt intake, type 2 diabetes mellitus) on the efficacy of ACE inhibitors in patients with arterial hypertension in a pilot study, and to determine the feasibility of genotyping for predicting achievement of target blood pressure.

MATERIALS AND METHODS. A pilot pharmacogenetic study was conducted with the participation of 90 ambulatory patients of both sexes with newly diagnosed arterial hypertension in the period from February to May 2025. Genotyping results of blood samples was tested for Hardy–Weinberg equilibrium with a correction for small groups. Quantitative data were tested for normality. The correlation was assessed using Fisher’s exact test (95% CI) with Cramér’s V for strength of association. An AUC-ROC prognostic model was built to assess the sensitivity and specificity of the effect of genotype on achieving target blood pressure (BP) <140/90 mmHg.

RESULTS. After receiving ACE inhibitor therapy, 39 patients achieved target blood pressure values (II — 34 (87.2%); ID — 5 (12.8%); DD — 0 (0%)), while 51 patients did not (II — 1 (0.7%); ID — 33 (67.4%); DD — 17 (33.3%)). The poly­morphic ACE gene D allele (rs1799752) was significantly associated with failure to achieve target BP on ACE inhibitor therapy (Fisher’s exact test, p<0.001; Cramér’s V=0.82). ROC analysis of the number of D alleles showed high discriminatory ability for predicting target BP failure (AUC=0.947; 95% CI: 0.899–0.996). Among confounders, excess salt intake was significantly associated with target BP failure (p<0.05), whereas sex, age, type 2 diabetes mellitus, smoking, and overweight showed no significant association (p>0.05).

CONCLUSIONS. Carriage of the ACE gene D allele (rs1799752) and excess salt intake were associated with an increased risk of failing to achieve target BP on ACE inhibitor therapy, while other confounders demonstrated no clinically significant predictive role. Because of the small sample size and homogeneity, these findings should be considered preliminary and require confirmation in larger multicenter studies.