Leukodystrophies are inherited neurodegenerative disorders characterized by progressive white matter damage, historically lacking effective treatments beyond symptomatic management and hematopoietic stem cell transplantation. This review analyzes contemporary biotechnological strategies, including gene therapy, cell-based approaches, and antisense oligonucleotides. Approved products like Libmeldy for metachromatic leukodystrophy and Skysona for adrenoleukodystrophy demonstrate that ex vivo lentiviral modification of autologous stem cells can stabilize neurological function when administered early. In vivo gene therapy using AAV vectors and antisense oligonucleotides targeting toxic protein accumulation show encouraging results in clinical studies. Despite challenges regarding blood-brain barrier delivery and immunogenicity, recent advances indicate a paradigm shift toward personalized genomic medicine. These innovations offer potential to halt disease progression and improve long-term outcomes for patients with previously untreatable conditions. 

Cognitive disorders (CDs) are among the most disabling components of the clinical picture of schizophrenia spectrum disorders (SSDs) and lead to a pronounced decline in the quality of life, as well as in social and occupational functioning of patients. CDs in patients with SSDs may be primary or secondary, with the latter developing during antipsychotic (AP) therapy. Individual predisposition to AP-induced CDs may arise from genetically rooted features of AP pharmacokinetics — in particular, the functional state of the efflux transporter P-glycoprotein (P-gp), encoded by the ABCB1 gene. This narrative review demonstrates that three single nucleotide variants of the ABCB1 gene (3435C>T, 1236C>T, and 2677G>T/A) have a proven effect on P-gp expression and substrate specificity. Carriage of the non‑functional TTT haplotype — the most common alongside the “wild‑type” CGC haplotype — is associated with increased AP concentrations in the blood and brain tissue, leading to enhanced neurotoxic adverse drug reactions (ADRs). Analysis of clinical studies confirms an association between non‑functional ABCB1 genotypes and haplotypes and an increased risk of ADRs to AP therapy. However, direct evidence linking ABCB1 haplotypes to neurocognitive outcomes in SSD has not yet been found. The association of certain ABCB1 haplotypes with AP-induced CDs is theoretically justified but requires clinical confirmation in prospective studies. Preventive pharmacogenetic testing for the ABCB1 gene appears to be a promising tool for personalizing АР therapy in patients with SSDs. It enables the identification of patients at risk for CDs prior to treatment initiation and allows adjustment of drug selection and dosing regimen. 

The definition of cardiogenic cognitive disorders (CCD) was first proposed in the mid20th century, but in subsequent years it was unjustifiably omitted from current clinical guidelines. Preclinical and clinical studies using modern methods of laboratory, functional, and radiological diagnostics confirm the significance and specific features of CCD development compared with those in cerebrovascular pathology. The pathophysiological mechanisms of CCD associated with acute myocardial infarction (AMI) include vascular dysregulation, atherosclerosis, platelet activation, microinfarctions, perivascular inflammation, impaired hemostasis, and a dysfunctional neurohumoral response. These mechanisms may lead to the occurrence of clinically silent microinfarctions, as well as impaired functionality of the white matter in the cerebral cortex. Such pathologies can cause cerebral hypoperfusion and microvascular ischemia, which in turn contributes to the enlargement of periventricular spaces and the development of cerebral amyloid angiopathy, and also leads to hippocampal sclerosis. Objective: To study the role of circulating microRNAs as epigenetic biomarkers of cognitive disorder associated with acute myocardial infarction in an animal model. Materials and Methods: At the first part of this experimental study, the dynamics of cognitive deficit and neurological status were studied in sexually mature Wistar rats. The total sample of experimental animals was divided into three groups, including the study group — AMI without therapy (n1 = 10), the comparison group — AMI with CCD therapy (n2 = 15), and the control group — without AMI and without therapy (n3 = 10). The observation groups were divided in equal numbers for the study of miR-19b-3p and miR-134-5p. The experimental model of AMI according to the method of N. Elmali was used. Blood sampling from the tail vein and assessment of cognitive functioning (the Morris test) and neurological deficit (neuropsychological test — NSS) were performed before the experiment and 10 days later. Three strategies were used for the treatment of early CCD: monotherapy with rosuvastatin, monotherapy with Prospekta®Vet, and combination therapy with rosuvastatin and Prospekta®Vet. To exclude the error of multiple comparisons before pairwise comparison using the Mann–Whitney test, all groups compared with each other were preliminarily compared using the Kruskal–Wallis test. Results: Baseline indicators of locomotor activity and cognitive functions according to the Morris test, as well as neurological status according to the NSS scale, were comparable in all groups (pvalue > 0.05). On day 10 after AMI modeling, no statistically significant changes in the parameters of the Morris test (speed, time in the target sector, distance, platform search time) were detected in any of the groups (p-value > 0.05). At the same time, significant intergroup differences were found according to the NSS test (p-value = 0.018, the Kruskal–Wallis test), due to an increase in neurological deficit in the subgroup receiving Prospekta®Vet monotherapy compared with the control group (pvalue = 0.003) and the AMI group without therapy (p-value = 0.005). Analysis of the dynamics of neurological symptoms (difference in NSS test scores) confirmed a trend toward its increase in the Prospekta®Vet monotherapy group, which was significantly higher than in the combination therapy group (p-value < 0.05). In 40% of animals in the AMI group without therapy and the Prospekta®Vet monotherapy group, moderate neurological deficit developed, whereas in the subgroups receiving rosuvastatin and combination therapy with rosuvastatin and Prospekta®Vet, this indicator was significantly lower. Conclusions: The present study successfully tested the AMI model according to the method of N. Elmali for studying CCD associated with AMI, revealing reproducible neurological deficit in the absence of gross cognitive deficit in experimental animals in the acute period. The most promising therapeutic strategy for the correction of early CCD associated with AMI is the combined administration of rosuvastatin and Prospekta®Vet at moderate therapeutic doses. To translate the obtained results into real clinical practice, a further "bridging" clinical study involving middle-aged adults with AMI is required.

Antipsychotic (AP) polypharmacy is used in 25–35% of patients with schizophrenia spectrum disorders (SSDs) and in up to 50% of patients with treatment-resistant schizophrenia, although the additive effect of two APs on platelet hemostasis and systemic inflammation (SI) remains insufficiently studied. Materials and Methods: An open cross-sectional observational pilot study included 72 adult inpatients with SSDs (International Classification of Diseases, 10th revision, ICD10: F20–F29): 33 patients receiving clozapine monotherapy and 39 patients receiving clozapinebased duotherapy (haloperidol, aripiprazole, risperidone, cariprazine, paliperidone, zuclopenthixol or trifluoperazine were prescribed as the second AP). Clinical, anamnestic, psychometric (Positive and Negative Syndrome Scale, PANSS; Columbia-Suicide Severity Rating Scale, C-SSRS; Clinical Global Impression — Severity, CGI-S), anthropometric and laboratory (complete blood count with platelet indices, C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), liver enzymes, lipid profile, glucose) methods were used, together with the calculated hematological indices: the neutrophil-to-lymphocyte ratio (NLR), the platelet-to-lymphocyte ratio (PLR), the monocyte-tolymphocyte ratio (MLR), the systemic immune-inflammation index (SII) and the systemic inflammation response index (SIRI). Results: The AP duotherapy was associated with significantly higher values of SI biomarkers: SII (1157 vs 896; p-value = 0.047), NLR (3.22 vs 2.51; p-value = 0.038), CRP (4.8 vs 2.5 mg/L; p-value = 0.029), ESR (16 vs 10 mm/h; p-value = 0.041) and absolute neutrophil count (p-value = 0.032). Platelet activation biomarkers were also higher: mean platelet volume (MPV) (10.2 vs 9.7 fL; p-value = 0.048), platelet distribution width (PDW) (12.3 vs 11.4 fL; p-value = 0.039) and platelet large cell ratio (P-LCR) (28.1% vs 24.5%; p-value = 0.027), whereas the platelet count (PLT) and plateletcrit (PCT) did not differ significantly. Total cholesterol (p-value = 0.047) and low-density lipoprotein cholesterol (p-value = 0.033) were higher in the duotherapy group. The magnitude of the additive effect depended on the second AP: the lowest values of SII, NLR and CRP were observed for the combinations of clozapine with aripiprazole and cariprazine, and the highest for the combinations with zuclopenthixol, haloperidol, risperidone and paliperidone. No significant correlations were found between the laboratory biomarkers studied and the scores of PANSS, C-SSRS and CGI-S (ρ from −0.058 to 0.187; p-value > 0.05 for all). Conclusion: In this pilot study, clozapine-based duotherapy was associated with a more pronounced inflammatory, prothrombotic and atherogenic laboratory profile than clozapine monotherapy, independently of the severity of psychopathology. When duotherapy of SSDs is required, co-administration of clozapine with aripiprazole or cariprazine appear preferable. Co-administration of clozapine with haloperidol, zuclopenthixol, risperidone or paliperidone require laboratory monitoring of the hematological biomarkers of platelet hemostasis and SI. 

The article presents two clinical cases demonstrating the use of intravenous valproic acid for the management of psychomotor agitation in inpatients with psychiatric disorders resistant to standard anxiolytic and antipsychotic treatment. Valproic acid was administered via intravenous drip at doses of 1.0–2.0 g per day for up to five consecutive days in a regimen analogous to that used for the treatment of status epilepticus. The cases illustrate that valproic acid effectively reduced psychomotor agitation without fundamentally altering the underlying psychopathological structure, thereby facilitating more accurate diagnostic assessment and enabling subsequent optimization of maintenance therapy. Temporary withdrawal of psychotropic medications during intravenous valproate administration appeared to overcome pharmacological resistance, and subsequent switching to the oral valproate formulation or reintroducing antipsychotics helped sustain the effect. We propose that the efficacy of this approach derives not only from valproic acid's established GABA-mimetic and membrane-stabilizing pharmacodynamics but also from its favorable pharmacokinetic properties during intravenous administration, which may potentiate inhibitory effects on hyperactive neural networks. These findings suggest that intravenous valproic acid represents a valuable strategy for managing treatment-resistant psychomotor agitation across diverse psychiatric diagnoses, warranting further controlled studies.