Search Results (402)

Pulmonary hypertension (PH) is a progressive, multifactorial syndrome characterized by elevated pulmonary arterial pressure and right heart dysfunction, associated with significant morbidity, impaired quality of life, and poor prognosis. Advances in classification, hemodynamic definitions, and targeted pharmacotherapies have improved understanding and management, yet therapeutic challenges persist across the five World Health Organization groups of PH. Historically, exercise was discouraged due to concerns about adverse hemodynamic effects, but growing evidence has suggested that structured, supervised training is safe and beneficial. Randomized trials and meta-analyses show improvements in six-minute walk distance, peak oxygen uptake, right ventricular function, ventilatory efficiency, and health-related quality of life, with a low incidence of adverse events. Physiological adaptations include favorable cardiac remodeling, enhanced endothelial function, improved skeletal and respiratory muscle performance, and improved neurohormonal activity. Despite this evidence, barriers such as patient fears, limited clinical expertise, and restricted access to specialized rehabilitation programs hinder widespread implementation. Current guidelines recommend supervised exercise as part of pulmonary rehabilitation for patients with stable PH, supporting its role as an adjunct to pharmacotherapy. This descriptive review briefly summarizes the pathophysiology of PH, phenotype-related differences and current therapeutic approaches, and the beneficial adaptations to exercise training, with the aim of informing exercise specialists and supporting safer, more effective integration of exercise-based rehabilitation into patient care. Full article

Background: Congenital heart defects (CHD) are the most common congenital malformations and often require complex, lifelong pharmacotherapy. In pediatric CHD populations, multidrug regimens targeting cardiac function and comorbidities predispose patients to polypharmacy. At the molecular level, concomitant drug use increases the risk of pharmacokinetic and pharmacodynamic interactions. Methods: This study aimed to characterize medication patterns and assess polypharmacy and potential drug–drug interactions in patients with CHD. A cross-sectional online survey was conducted in collaboration with the German National Register for Congenital Heart Defects (NRCHD) between November and December 2021. Patients aged 6–17 years with CHD were eligible for inclusion. Participants reported their current medications in open-ended questions. Drugs were categorized into pharmacological classes, and common drug combinations were evaluated for potential interactions. Results: Of 894 participants included in the analysis, 372 reported current medication use. Among these, 179 (48.1%) met criteria for polypharmacy (≥2 drugs). Polypharmacy was more frequent in patients with higher disease severity and comorbidity burden. Several drug combinations showed potential for clinically relevant pharmacokinetic and pharmacodynamic interactions, including mechanisms involving renal electrolyte handling, altered protein binding, cytochrome P450-mediated metabolism, and additive pharmacodynamic effects. Conclusions: Children with CHD are exposed to complex multidrug regimens with a considerable interaction risk, underscoring the need for systematic medication review and mechanistically informed pharmacological management in pediatric CHD care. Full article

Cardiovascular–kidney–metabolic (CKM) syndrome is a systemic, interdependent disorder arising from the convergence of metabolic dysfunction, chronic kidney disease, and cardiovascular pathology. Anchored in the Developmental Origins of Health and Disease (DOHaD) framework, this review advances a “parallel hit” model, primarily based on evidence from experimental animal studies, particularly rodent models, posited that early-life environmental insults concurrently program structural and functional vulnerabilities in both renal and central nervous system hubs. These early perturbations prime susceptibility long before clinical manifestations emerge. CKM progression is conceptualized as a two-stage trajectory, with an initial phase of parallel programming affecting kidney and brain development, followed by a transition to maladaptive bidirectional crosstalk. In the later phase, heightened efferent sympathetic outflow and aberrant afferent renal signaling—potentiated by uremic toxin accumulation, neuroinflammation, and blood–brain barrier disruption—drive a self-perpetuating cycle that accelerates cardiorenal and metabolic injury. Key integrative mechanisms, including oxidative stress, chronic low-grade inflammation, mitochondrial dysfunction, and gut microbiota dysbiosis, serve as convergent pathways linking early-life exposures to adult CKM phenotypes. These pathways not only sustain disease progression but also represent actionable therapeutic targets. Importantly, this framework underscores the translational potential of early-life “reprogramming” strategies. Interventions such as precision nutrition, antioxidant supplementation, microbiota-directed therapies (including prebiotics, probiotics, and postbiotics), and mechanism-based pharmacotherapies may mitigate or reverse maladaptive programming. However, much of the current mechanistic evidence remains preclinical, and further human studies are needed to validate these pathways and therapeutic approaches. Collectively, this dual-hub paradigm reframes CKM syndrome as a life-course continuum rather than a late-stage comorbidity cluster, emphasizing the necessity of early, mechanism-driven interventions to stabilize the brain–kidney axis and improve long-term cardiovascular–kidney–metabolic outcomes. Full article

Background: Gentamicin-induced nephrotoxicity limits clinical pharmacotherapy and involves multiple converging stress-response pathways. Ellagic acid (EA) has renoprotective potential, yet its role in coordinating endoplasmic reticulum (ER) stress-mediated apoptosis, autophagy, and inflammation remains unclear. We hypothesized that EA co-treatment would protect the kidney by modulating ER stress-dependent pathways and associated inflammatory and adaptive signaling. Methods: For an integrated mechanistic analysis in a rat model of gentamicin nephrotoxicity, 40 male Sprague-Dawley rats were assigned to control, gentamicin (100 mg/kg), EA (100 mg/kg), and gentamicin + EA groups for 14 days. Renal function, oxidative stress, inflammatory mediators, ER stress markers, apoptosis, autophagy, tubular injury markers, and histopathological changes were assessed. Results: Gentamicin induced renal dysfunction, tubular injury, and ER stress across all unfolded protein response (UPR) branches (IRE1α, PERK, ATF6), C/EBP homologous protein (CHOP)-associated apoptosis, dysregulated autophagy, and upregulated kidney injury molecule-1 (KIM-1). A selective inflammatory signature was observed, with increased cyclooxygenase-2 (COX-2) and interleukin-6 (IL-6), whereas tumor necrosis factor-alpha (TNF-α) and interleukin-1 beta (IL-1β) remained unchanged. Co-administration of ellagic acid with gentamicin significantly improved renal function markers compared to the gentamicin group. In contrast, ellagic acid alone did not show significant differences compared to the control group. Notably, gentamicin induced compensatory upregulation of nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) expression, while ellagic acid co-treatment attenuated this compensatory upregulation, likely secondary to reduced oxidative stress burden. Conclusions: This study provides integrated evidence that ER stress is closely associated with gentamicin nephrotoxicity. The key novel findings include selective suppression of IL-6, modulation of the apoptosis-autophagy balance, and attenuation of Nrf2/HO-1 signaling without direct reactive oxygen species (ROS) scavenging, demonstrating a multi-target framework for EA’s renoprotective effects. These findings suggest that ellagic acid mitigates renal injury in a context-dependent manner rather than confirming a direct causal mechanism. Full article

Cardiovascular diseases (CVDs) remain the leading global cause of morbidity and mortality, imposing an increasing clinical and socioeconomic burden. Despite significant therapeutic advances, optimal control of risk factors and long-term outcomes remain challenging, particularly in patients with complex comorbidities. This narrative review provides a comprehensive and up-to-date synthesis of pharmacological options across major cardiovascular domains, with a specific focus on hypertension, heart failure, arrhythmias, and hypertrophic cardiomyopathy, conditions in which hemodynamic, neurohormonal, and electrophysiological pathways play central roles. We summarize mechanisms of action, clinical evidence, safety profiles, and guideline-based indications of established therapies, highlighting their relevance to vascular tone regulation, neurohormonal modulation, endothelial signaling, and myocardial function, the mechanistic axes that intersect with pathways implicated in pulmonary vascular disease (PVD). In addition, we discuss emerging therapeutic targets and innovative agents such as renin-angiotensin-aldosterone system silencers, endothelin pathway modulators, SGLT2 inhibitors, soluble guanylate cyclase stimulators, myosin inhibitors, and other mechanism-based approaches. Current challenges and unmet clinical needs are examined in the context of translational relevance for PVD and the broader goal of advancing individualized pharmacotherapy. Continued therapeutic innovation targeting shared vascular, metabolic, and neurohormonal pathways holds promise for improving outcomes across both systemic and pulmonary vascular diseases. Full article

Background: Rheumatoid arthritis (RA) is a persistent autoimmune condition defined by widespread synovial tissue inflammation and structural joint deterioration, with an estimated global prevalence between 0.5% and 3%. The disease predominantly targets synovial joints, resulting in progressive functional impairment when therapeutic intervention is delayed or inadequate. Objective: This review aims to comprehensively examine the contributing risk factors, underlying pathophysiological processes, and recently developed immunoengineering-based therapeutic strategies applicable to the clinical management of rheumatoid arthritis. Methods: A structured review of peer-reviewed literature was undertaken through PubMed, utilizing a targeted search strategy incorporating the terms ‘rheumatoid arthritis’ and ‘immunoengineering.’ Filters were applied to restrict results to English-language publications from peer-reviewed sources. The review emphasized studies investigating genetic susceptibility, environmental determinants, immune cell behaviour, and novel therapeutic advances in RA management. Results: Multiple interdependent risk factors underpin RA development, most notably genetic variants including HLA-DRb1 alleles, alongside demographic influences such as biological sex and advancing age, as well as obesity and pathogenic microbial exposure. These factors collectively initiate a self-amplifying inflammatory process characterized by protein citrullination and the subsequent generation of anti-citrullinated protein antibodies (ACPAs) and rheumatoid factor (RF). The ensuing immune dysregulation—driven principally by monocyte and T-lymphocyte infiltration—propagates synovial inflammation and progressively destroys cartilaginous and bony structures. Conclusions: While considerable progress has been achieved in RA pharmacotherapy, existing treatments remain constrained by systemic side effects and incomplete therapeutic responses. Emerging immunoengineering strategies offer a targeted approach to modulating the molecular and immunological milieu of affected joints, providing improved therapeutic precision. Continued investigation in this area is anticipated to yield novel clinical pathways capable of substantially enhancing patient outcomes in rheumatoid arthritis care. Full article

Purpose: To review the long-term cardiovascular risks associated with three common perinatal endocrine disorders—gestational diabetes mellitus (GDM), hypertensive disorders of pregnancy (HDP), and thyroid dysfunction (including postpartum thyroiditis)—and to identify opportunities for early risk stratification and prevention. Materials and Methods: We conducted a structured literature search of PubMed and Web of Science for peer-reviewed articles published between January 2000 and December 2025. Search terms included combinations related to GDM, HDP, thyroid dysfunction, and cardiovascular disease (CVD). We prioritized prospective cohort studies, meta-analyses, systematic reviews, and major clinical guidelines. Key findings were synthesized thematically. Results: GDM is associated with a 1.6- to 2-fold increased risk of future CVD, HDP with a 1.8-fold increase, and subclinical hypothyroidism with a two-fold increase. These risks persist for decades, are independent of traditional risk factors, and are amplified by obesity, recurrence, and social determinants of health. Converging pathophysiological mechanisms include persistent insulin resistance, chronic low-grade inflammation, endothelial dysfunction, autonomic dysregulation, epigenetic modifications, and subclinical myocardial remodeling. The placenta serves as a central endocrine–cardiovascular interface, releasing anti-angiogenic factors, pro-inflammatory cytokines, and exosomal microRNAs. Despite this evidence, postpartum screening uptake remains below 50%, care is fragmented, and pregnancy history is not incorporated into CVD risk calculators. Conclusion: A life-course approach integrating structured postpartum screening (6–12 weeks and annually), lifestyle interventions, targeted pharmacotherapy, and multidisciplinary cardio-obstetrics programs is urgently needed to reduce the global burden of premature heart disease, stroke, and heart failure in women. Full article

Aim: This review summarizes the current evidence on cognitive impairment in patients with glioma, with particular emphasis on the underlying mechanisms, methods for objective assessment of cognitive deficits, and currently available therapeutic strategies. Methods: Relevant literature was identified through searches of the PubMed, Cochrane Library, and Google Scholar databases. Studies addressing the mechanisms, assessment, and management of cognitive impairment in patients with glioma published between January 2000 and February 2026 were reviewed to summarize current evidence and emerging therapeutic strategies. A structured literature search and study selection process was performed. Results: Cognitive deficits represent a heterogeneous clinical problem affecting the majority of patients diagnosed with gliomas. These impairments are multifactorial in origin, resulting both from direct infiltration of white matter by the tumor process and from the cumulative toxicity of treatment modalities, including radiotherapy, chemotherapy, corticosteroid therapy, and long-term use of antiseizure medications. Analysis of the current literature confirms that modern radiotherapy techniques (e.g., hippocampal-sparing approaches) and isocitrate dehydrogenase (IDH)-targeted therapies, such as vorasidenib, may significantly delay cognitive decline. Standardized neuropsychological batteries for the objective assessment of these disturbances remain the preferred tools recommended by the International Cognition and Cancer Task Force (ICCTF). Regarding therapeutic interventions, potential benefits have been demonstrated for supportive pharmacotherapy (including memantine), while individualized neuropsychological rehabilitation has also been shown to improve patients’ quality of life. Full article

Background: The growing complexity and cost of oncohematological treatments has created an urgent need for standardized methodologies capable of enabling inter-institutional comparisons of healthcare expenditure within homogeneous patient groups. Cancer-related pharmaceutical costs vary substantially depending on tumour type, disease stage, and therapeutic approach, making cross-institutional benchmarking challenging due to heterogeneity in patient populations and clinical practice patterns. Therefore, integrating cost analysis with clinically meaningful patient stratification is essential to improve resource allocation and outcome evaluation. Methods: A multicentre working group comprising four tertiary hospitals in Madrid (Spain) was established to develop and preliminarily evaluate a novel classification system for adult oncohematological patients. A standardized methodology was designed to stratify patients into homogeneous groups (PATONCO categories) based on tumor location, therapeutic objective, and clinically relevant biomarkers. A cost indicator was defined as the average cost per patient per month for each PATONCO category. Data were extracted from pharmacy dispensing systems and analyzed using descriptive and inferential statistics, including Kruskal–Wallis and post hoc Dunn tests. Results: A total of 3659 patients were included (3168 oncology; 491 hematology), distributed across 62 programmes (54 oncology; 8 hematology). The PATONCOS tool enabled the identification and validation of a cost indicator (average cost/patient/month per category), allowing inter-hospital comparison. Significant differences in costs were observed across most high-prevalence categories, reflecting variability in drug selection within homogeneous patient groups, as documented by the differential use of specific therapeutic agents across centers. The model demonstrated its capacity to detect intra-group homogeneity and inter-group variability, improving the identification of high-cost patient subgroups and supporting benchmarking across centers. Conclusions: The PATONCOS tool provides a novel, clinically oriented stratification methodology that integrates pharmacotherapy, biomarkers, and disease stage with economic evaluation. This approach enables more accurate comparisons of oncology treatment costs between institutions and may support data-driven decision-making in resource allocation. Its implementation may contribute to more sustainable healthcare systems by aligning clinical practice with economic outcomes. Full article

Background and Objectives: Mental illnesses place a substantial burden on healthcare systems and often require complex pharmacological management. However, it remains unclear whether early antipsychotic polypharmacy independently predicts length of stay after adjusting for important confounders. This study aimed to investigate drug utilization patterns, including polypharmacy and drug–drug interactions (DDIs), assess anticholinergic burden, and identify predictors of the length of hospital stay in a psychiatric inpatient setting. Materials and Methods: This retrospective, observational study was conducted at Bolu İzzet Baysal Mental Health and Diseases Hospital with 280 adult patients admitted during 2022. Medication data were extracted from electronic medical records based on medication orders within the first 72 h of admission. Potential DDIs were assessed using Lexi-Interact, and anticholinergic burden was calculated using the ACB, ADS, and ARS scales. Predictors of the length of stay (LOS) were modelled using negative binomial regression. Results: The mean age of the population was 38.65 ± 13.86 years, and 62.1% were male. Polypharmacy was present in 37.9% of patients, while antipsychotic polypharmacy was observed in 63.9%. Potential DDIs were identified in 88.9% of patients, with a significantly higher prevalence in those with polypharmacy. Mean ACB and ADS scores were high at 5.56 ± 3.32 and 4.15 ± 2.79, respectively. Multivariable regression analysis revealed that antipsychotic polypharmacy was the primary independent predictor of prolonged hospitalization, associated with a 20.9% increase in LOS (IRR = 1.209, 95% CI: 1.044–1.400, p = 0.011). While age was also statistically significant (IRR = 1.006, 95% CI: 1.001–1.012, p = 0.019), its clinical impact was minimal, representing only a 0.6% increase in LOS per year. Conclusions: Antipsychotic polypharmacy within the first 72 h of admission is a significant independent predictor of prolonged hospitalization. The high prevalence of drug interactions and substantial anticholinergic burden highlight the need for systematic early medication review. Instead of general monitoring, targeted medication therapy review focusing on antipsychotic polypharmacy in the early period of admission may be essential to identify and mitigate modifiable risk factors for prolonged hospitalization, thereby optimizing pharmacotherapy in psychiatric inpatient settings. Full article

Background/Objectives: Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have transformed type 2 diabetes mellitus (T2DM) and obesity care, with clinical trials demonstrating weight loss exceeding 15%. However, real-world effectiveness lags trial efficacy, largely owing to high discontinuation rates. We characterize the global persistence gap and propose a framework integrating Medical Nutrition Therapy (MNT) to improve adherence. Methods: We conducted a narrative review of real-world evidence from North America, Europe, Asia, and Latin America, synthesized with physiological, nutritional, and behavioral data to distinguish established contributors to discontinuation from strategies that remain partly extrapolated from related populations. Results: Global persistence varies widely: from approximately 75–80% at 12 months in reimbursed T2DM cohorts (Sweden, Denmark) to below 10% in obesity-focused or high out-of-pocket-cost settings (Poland, Colombia), with intermediate rates in the United States and United Kingdom; in several cohorts, persistence falls below 15% by 24 months. The primary drivers are gastrointestinal intolerance and economic barriers. Meal size, dietary composition, and gastric-emptying effects influence gastrointestinal tolerability; inadequate protein intake during rapid weight loss raises concern for lean mass loss. Conclusions: Pharmacotherapy alone is unlikely to sustain long-term obesity management. Narrowing the persistence gap will require an integrated care model in which structured nutritional support—targeting protein intake, micronutrient density, and gastric-sparing feeding—is systematically offered rather than treated as an optional adjunct, while recognizing that most supporting evidence is extrapolated from primary trials in obesity and cardiometabolic disease rather than derived from GLP-1–specific randomized trials. Full article

Background: Glucagon-like peptide-1 receptor agonists (GLP-1RAs) and dual glucose-dependent insulinotropic polypeptide (GIP)/GLP-1 receptor agonists have transformed obesity treatment, producing substantial weight loss during active therapy. However, real-world effectiveness may be limited by gastrointestinal adverse events, reduced dietary intake, fat-free mass loss as part of total weight reduction, and weight regain after discontinuation. Methods: This narrative review synthesizes current pharmacological, nutritional, gastrointestinal, body-composition, and implementation evidence to propose an evidence-informed nutrition-first framework for patients receiving incretin-based therapy for obesity. Results: We translate pharmacologic mechanisms into practical dietary strategies, including protein prioritization, structured meal patterns, hydration and fiber management, symptom-targeted interventions, resistance-training support, and maintenance planning. Because direct trials of structured nutrition interventions in GLP-1RA- or dual incretin-treated populations remain limited, several recommendations are extrapolated from the broader obesity, caloric restriction, body-composition, gastrointestinal, and expert-consensus literature. Conclusions: Integrating structured nutrition care into pharmacotherapy pathways may help address meal-related symptom burden, support protein and fluid adequacy, identify patients at higher nutritional or body-composition risk, and prepare patients for long-term weight-management behaviors. Embedding practical nutrition management within multidisciplinary obesity care may help translate pharmacologic efficacy into durable, patient-centered outcomes. Full article

Metabolic dysfunction-associated steatotic liver disease (MASLD) is the leading cause of global chronic liver disease, with a prevalence of approximately 30%. This review outlines the diagnostic transition from the exclusionary non-alcoholic fatty liver disease (NAFLD) framework to the affirmative MASLD nomenclature, which mandates the presence of at least one of five specific cardiometabolic risk factors (CMRFs) to prioritize active pathophysiology. Beyond hepatic complications, MASLD drives systemic metabolic failure, significantly elevating risks for type 2 diabetes, hepatocellular carcinoma, and cardiovascular disease, the primary cause of mortality in this cohort. Clinical management relies on a standardized, two-tier risk-stratification pathway for advanced fibrosis. Primary care triage utilizes the Fibrosis–4 (FIB–4) index; a score < 1.3 excludes advanced disease via a high negative predictive value, whereas indeterminate or high scores require secondary validation via vibration-controlled transient elastography (VCTE) or the enhanced liver fibrosis (ELF) test to guide specialist referral. Although lifestyle modifications, principally a 7–10% weight reduction and Mediterranean diet adherence, remain foundational, management has transitioned toward disease-modifying pharmacotherapies. A pivotal breakthrough occurred with the 2024 FDA approval of resmetirom, a selective thyroid hormone receptor-beta (THR-β) agonist, for non-cirrhotic metabolic dysfunction-associated steatohepatitis (MASH) with moderate-to-advanced fibrosis. Concurrently, the emergence of GLP-1 receptor agonists and multi-incretin mimetics offers a personalized, multi-target approach simultaneously addressing hepatic inflammation, glycemic control, and adiposity. Full article

Atherosclerosis is a chronic inflammatory arterial disease and the primary underlying cause of cardiovascular morbidity and mortality worldwide. Its development and progression are driven by a mechanistically interconnected triad of endothelial dysfunction, oxidative stress, and vascular inflammation. Current pharmacotherapy, primarily focused on low-density lipoprotein cholesterol (LDL-C) reduction through statin-based and adjunctive therapies, does not fully address the residual inflammatory and calcific components of atherosclerotic risk. Menaquinone-7 (MK-7), a long-chain isoform of vitamin K2 with superior bioavailability and extrahepatic tissue distribution, has emerged as a multi-target modulator of atherogenic processes. Its classical function is to serve as a cofactor for the gamma-carboxylation of vitamin K-dependent proteins (VKDPs), principally matrix Gla protein (MGP), the primary endogenous inhibitor of vascular calcification. Beyond this established pathway, a growing body of experimental evidence indicates that MK-7 may modulate endothelial nitric oxide (NO) production through carboxylation-dependent activation of Growth Arrest-Specific Protein 6 (Gas6) and suppress lipid peroxidation and ferroptosis via Ferroptosis Suppressor Protein 1 (FSP1)-mediated reduction of vitamin K hydroquinone (VKH₂). In addition, it may attenuate nuclear factor kappa-B (NF-κB)-driven inflammatory gene transcription in vascular cells. Previous reviews mainly focused on how vitamin K2 influences vascular calcification and cardiovascular outcomes. However, emerging mechanistic evidence linking MK-7 to endothelial dysfunction, oxidative stress, ferroptosis, and vascular inflammation has not been comprehensively integrated. This review summarizes the current knowledge of in vitro, animal, observational, and randomized controlled trial evidence for MK-7 in the context of atherosclerosis. It particularly emphasises mechanistic pathways, the strength of evidence, and translational limitations, highlighting the lack of direct human vascular evidence in several areas. Full article

Background/Objectives: Bipolar disorder affects about 40 million people worldwide, and the greatest burden of the disease is associated with depressive episodes. About 25% of patients experience drug-resistant depression, in which standard treatment turns out to be insufficient, and monotherapy often does not bring full remission. Despite the use of second-generation antipsychotics, the effectiveness of therapy in TRBD remains limited, which necessitates rational polypharmacotherapy and augmentation strategies. The paper discusses the receptor mechanisms of drug combination, current therapeutic regimens and new interventions such as ketamine acting on the glutamate anergic system. The aim was to synthetically compare the efficacy and safety of available augmentation strategies and polypharmacotherapy. Methods: The material consists of published clinical, observational and randomized trials on pharmacotherapy of drug-resistant bipolar depression, including atypical neuroleptics, ketamine, pramipexole, modafinil, lamotrigine, celecoxib and memantine. The authors analyze receptor mechanisms, neurobiological data and clinical trial results, comparing them with current definitions of TRBD according to ISBD and CINP. Biomarker data, such as the Systemic Immune-Inflammation Index, and the results of neuroimaging and metabolomic studies were also used in the work. Results: The analysis showed that atypical neuroleptics showed limited efficacy and high rates of side effects, while ketamine has the fastest and most pronounced antidepressant effect with a low risk of phase change. Pramipexole has shown promise in terms of long-term efficacy, but its use reduces the high risk of induction of mania and impulse control disorders. Celecoxib as an anti-inflammatory therapy significantly increased response and remission rates compared to escitalopram alone, and memantine showed only an early, short-term antidepressant effect. The results highlight that TRBD requires targeted polypharmacotherapy, with the most promising directions being glutamatergic modulation and anti-inflammatory therapies. Conclusions: Drug-resistant bipolar depression requires a departure from classical monotherapy in favor of rational, mechanistically justified polypharmacotherapy, targeting complex monoaminergic, glutamatergic and neuroinflammatory disorders. Available data indicate that ketamine has the greatest clinical potential among the current strategies, characterized by a rapid onset of action and a favorable safety profile compared to atypical neuroleptics or dopamine agonists. Modulation of inflammatory processes with the use of celecoxib also has promising results, which highlights the importance of biomarkers and personalization of therapy. However, further, large, and well-designed studies are needed to unambiguously determine optimal treatment strategies for TRBD and to verify the effectiveness of new pharmacological interventions. Full article