Search Results (430)

Background/Objectives: After menopause, hormonal, age-related, and lifestyle factors may adversely affect physical functioning and psychological well-being. This study compared immediate changes in physical function, psychological health, and health-related quality of life following a five-day Combined Marine Treatment Program (CMTP) with those observed under a usual-routine control condition. Methods: A parallel-group randomized controlled trial was conducted with 62 postmenopausal women allocated equally to the CMTP and control groups. The CMTP included coastal walking, resistance exercises, mindfulness meditation, and visits to local natural attractions. Participants in the control group continued their customary daily activities. The co-primary outcomes were the Timed Up and Go test and the Short Form-36. Secondary outcomes were grip strength, pinch strength, static balance, the 10-item Perceived Stress Scale, and the Beck Depression Inventory-II. Mixed repeated-measures analysis of variance was used to test whether temporal changes differed between groups. Trial registration was completed through the Clinical Research Information Service of the Republic of Korea (KCT0009741). Results: Changes over time differed significantly between groups for the Timed Up and Go test, grip strength, pinch strength, eyes-open sway area, eyes-closed sway area, eyes-closed sway velocity, and all self-reported outcomes. Post-intervention values differed significantly between groups for the Timed Up and Go test, pinch strength, both eyes-closed balance measures, and all self-reported outcomes. No adverse events were reported during the trial. Conclusions: Relative to the usual-routine condition, the five-day CMTP was associated with immediate changes in selected performance-based physical outcomes and broader changes across self-reported psychological and health-related quality-of-life outcomes. Brief multicomponent coastal health programs therefore warrant further study in postmenopausal women. Full article

Background/Objectives: Ketamine has attracted interest in psychiatry due to its rapid antidepressant effects, particularly in patients with inadequate response to conventional treatments. This scoping review maps ketamine’s neuropharmacology, mechanisms of action, clinical applications, safety, and use in psychiatric disorders. Methods: This scoping review was conducted according to the guidelines of Preferred Reporting Items for Systematic Reviews and Meta-Analyses Extension for Scoping Reviews. PubMed, Scopus, Web of Science, and Google Scholar were searched for English-language publications addressing ketamine pharmacology, clinical applications, and psychoactive effects. Included sources comprised randomized controlled trials, observational studies, systematic reviews, and relevant mechanistic studies, while non-English publications, editorials, commentaries, and studies without sufficient methodological information were excluded. Data were extracted using a structured data-charting form and synthesized narratively and thematically. Results: A total of 69 studies were included in the final synthesis. Ketamine demonstrated early improvements in depressive symptoms, especially in treatment-resistant depression (TRD), although the durability of benefits varied across studies. Intravenous racemic ketamine was the most extensively investigated administration route, while intranasal esketamine represents the primary approved formulation for TRD. Mechanistically, the drug acts through N-methyl-D-aspartate receptor antagonism and downstream modulation of glutamatergic signaling, synaptic plasticity and neural connectivity. Comparisons with conventional antidepressants and neuromodulatory interventions highlighted ketamine’s faster onset of action, although variability remained regarding long-term effects and treatment strategies. Conclusions: Ketamine represents an important rapid-acting treatment for TRD and severe depressive episodes associated with suicidal ideation. However, information regarding long-term efficacy and safety remains limited due to study heterogeneity, short follow-up periods, and variability in dosing protocols. Further research is needed to address gaps related to long-term outcomes, maintenance strategies, and optimal dosing approaches. Full article

Background/Objectives: Electroconvulsive therapy (ECT) remains the most effective biological treatment for treatment-resistant depression. Although its efficacy has been consistently demonstrated, the influence of seizure characteristics and treatment parameters on clinical outcomes in routine practice remains incompletely understood. This study aimed to evaluate the effectiveness of seizure threshold-titrated ECT in patients with treatment-resistant depression and to describe treatment outcomes in relation to seizure expression and technical treatment variables. Methods: We conducted a retrospective naturalistic study at the Department of ECT, Dr. Gh. Preda Clinical Psychiatric Hospital, Sibiu, Romania. Consecutive patients treated with ECT for treatment-resistant depressive episodes between March 2022 and December 2025 were included. Clinical outcomes were assessed before and after treatment using the Montgomery–Åsberg Depression Rating Scale (MADRS), Beck Depression Inventory (BDI), Mini-Mental State Examination (MMSE), and Global Assessment of Functioning Scale (GAF). Information regarding electrode placement, seizure threshold, seizure duration, the number of ECT sessions, and concomitant psychotropic medication was collected from medical records. Results: Nineteen acute ECT courses were available for outcome analysis. Depressive symptom severity improved significantly following treatment, with median MADRS scores decreasing from 38 (IQR 36–41) to 20 (IQR 9.5–24) (p < 0.001). A clinical response was observed in 57.9% of courses, while 36.8% achieved remission. Similar improvements were noted in self-reported depressive symptoms and overall functioning, with median BDI scores decreasing from 38 to 16 and median GAF scores increasing from 55 to 65. MMSE scores remained stable throughout treatment. Considerable variability was observed in both motor and EEG seizure durations; however, no consistent relationship between seizure duration and antidepressant response was identified. Discussion: The observed outcomes are consistent with previous evidence supporting ECT as an effective intervention for severe depressive illness. Functional improvement accompanied symptom reduction, while no decline in global cognitive performance, as assessed by the MMSE, was observed. In this cohort, seizure duration alone did not appear to provide meaningful information regarding treatment response. Conclusions: Seizure threshold-titrated ECT was associated with substantial clinical improvement in patients with treatment-resistant depressive episodes, accompanied by improved functioning and stable global cognitive performance. These findings support the continued use of individualized ECT protocols in routine clinical practice and highlight the need for further research on neurophysiological predictors of treatment outcome. Full article

Background: Deep brain stimulation (DBS) is a promising intervention for severe treatment-resistant OCD (TR-OCD), yet evidence of clinical efficacy remains inconsistent across heterogeneous study designs and anatomical target selection lacks standardization. Whether target choice influences clinical outcomes has not been systematically established, and prior meta-analyses have not characterized target-specific effects or predictors of response. Objectives: This systematic review and meta-analysis evaluated the efficacy of DBS versus sham stimulation in RCTs and its effectiveness in non-randomized studies, with OCD symptom severity, comorbid anxiety and depression, and global functioning as outcomes. Secondary objectives were to examine whether anatomical stimulation site influences therapeutic outcomes using systematic recategorization of reported targets, and to characterize the temporal dynamics of treatment response. Methods: Four databases (PubMed, Embase, Web of Science, CENTRAL) were searched through July 2025 following PRISMA 2020 guidelines. RCTs (active vs. sham DBS) and non-randomized studies reporting pre/post-DBS Y-BOCS scores were analyzed separately at three time points (≤12 months, >12 months, last follow-up). Stimulation targets were recategorized using active contact location and stereotactic coordinates. Random-effects models, meta-regression, RoB 2, ROBINS-I, and GRADE were applied. Results: Eight RCTs (n = 83) and 32 non-randomized studies (n = 321) were included. In RCTs, active DBS reduced Y-BOCS scores by 6.92 points (95% CI: 4.46–9.38; 18.3%; p < 0.001; I² = 62.93%) versus sham. Non-randomized studies demonstrated reductions of 13.83 points (95% CI: 11.01–16.52), 17.34 points (95% CI: 14.70–20.04), and 14.51 points (95% CI: 12.78–16.26; 43.5%; p < 0.001) at ≤12 months, >12 months, and last follow-up, respectively, with substantial heterogeneity (I² ≥ 89.79%). Responder and remission rates were 60.2% (95% CI: 52.8–67.2%; I² = 20.7%) and 36.4% (95% CI: 29.8–43.5%; I² = 12.1%), respectively. Anxiety (k = 7; d = 1.1; 95% CI: 0.72–1.56), depression (k = 24; d = 1.1; 95% CI: 0.80–1.26), and global functioning (k = 14; baseline GAF = 34.5; MD = 25.62; 95% CI: 22.18–29.03) improved significantly (all p < 0.001). In meta-regression, longer follow-up duration was the only significant predictor of Y-BOCS improvement (p = 0.042). Therapeutic effects varied substantially across anatomical stimulation sites. The anterior limb of the internal capsule (ALIC) and its ventral subdivision (vALIC) were most frequently stimulated. The inferior thalamic peduncle was associated with the largest mean Y-BOCS improvement (19.70 points; based on two trial arms only), nucleus accumbens stimulation did not reach the clinical response threshold (≥35% Y-BOCS reduction), and mediodorsal/ventral anterior thalamic stimulation showed no statistically significant benefit. Sensitivity analyses confirmed the robustness of primary estimates. Evidence quality was moderate (RCTs) and low (non-randomized studies). Conclusions: DBS significantly reduces OCD symptom severity in TR-OCD despite substantial heterogeneity, with greater improvements associated with longer follow-up duration and effects maintained for at least 30 months, alongside improvements in comorbid anxiety, depression, and global functioning. Not all anatomical stimulation sites are therapeutically equivalent, underscoring the importance of target selection. High-quality RCTs with standardized anatomical reporting are needed to consolidate the evidence base. Full article

Therapeutic inertia has been extensively examined in chronic medical conditions but remains insufficiently conceptualized and empirically studied in psychiatry. This structured narrative review examines therapeutic inertia as a multilevel and potentially bidirectional phenomenon arising when clinically relevant care is not reconsidered or modified despite unmet therapeutic goals and the availability of a reasonable and feasible alternative. A targeted PubMed search was supplemented by backward and forward citation searching, prioritizing psychiatric evidence and foundational literature on clinical decision-making under uncertainty. The review distinguishes therapeutic inertia from appropriate caution, watchful waiting, informed refusal, structural non-access, therapeutic nihilism, medical futility, therapeutic obstinacy, and evidence-based deprescribing. Potential determinants include cognitive and emotional mechanisms, diagnostic and prognostic uncertainty, adverse-effect concerns, patient preferences and previous experiences, therapeutic relationships, resource constraints, fragmented care, guideline structures, workload, and medicolegal culture. Clozapine underutilization in treatment-resistant schizophrenia represents the most compelling psychiatric example, while direct but more limited evidence is available in major depressive and bipolar disorders; applications to anxiety, obsessive-compulsive, substance-use, and non-pharmacological care remain largely hypothesis-generating. Strategies include explicit therapeutic goals, planned reassessment, measurement-based and guideline-informed care, shared decision-making, multidisciplinary review, improved access, clinical decision support, and audit and feedback. Future research should use operational definitions, experimental and observational designs, patient-centered outcomes, and real-world data to determine when treatment non-modification is inappropriate and whether corrective interventions improve care without promoting indiscriminate escalation, coercion, polypharmacy, or premature discontinuation. Full article

Major depressive disorder (MDD) is a prevalent psychiatric disorder in which epigenetic mechanisms, particularly DNA methylation (DNAm), may contribute to disease vulnerability and treatment response. Epigenome-wide association studies (EWAS) have increasingly investigated longitudinal methylomic changes associated with therapeutic interventions in depression; however, methodological heterogeneity limits comparability across studies. This critical review examined the methodologies and findings of longitudinal EWAS evaluating DNAm changes related to treatment response in MDD and treatment-resistant depression (TRD). A literature search identified seven studies published up to 20 June 2026. Six studies investigated non-pharmacological interventions, including electroconvulsive therapy, trauma-focused psychotherapy, and cognitive interventions, and one study explored pharmacotherapy. Considerable heterogeneity was observed regarding sample size, biospecimen type, methylation platforms, preprocessing pipelines, covariate adjustment, statistical modeling, and longitudinal sampling schedules. Most studies used Illumina EPIC array-based workflows and mixed-model analytical approaches, while one study employed sequencing-based methylation profiling. Overall, treatment-related methylation changes were modest and often limited to specific CpG sites or differentially methylated regions associated with immune, inflammatory, stress-related, and neurobiological pathways. Current evidence supports the feasibility of longitudinal EWAS approaches in depression research but highlights the need for larger cohorts, methodological standardization, and integration with multi-omics and clinical data to improve reproducibility and biomarker discovery. Full article

Background/Objectives: Psilocibin (PSY), a serotonergic hallucinogen, has attracted increasing scientific interest due to its therapeutic potential, particularly in treatment-resistant depression. In parallel with its growing clinical and research relevance, important questions have emerged regarding its safety profile, including potential effects on the liver, kidneys, cardiovascular system, and immune function. The aim of this narrative review was to systematically collect, critically appraise, and organize the dispersed evidence regarding potential multi-organ safety signals associated with PSY exposure. Methods: A narrative review was conducted including preclinical studies, pharmacological investigations, available clinical data, and published case reports, including reports of mushroom-related intoxications involving PSY-containing species. All available sources addressing potential toxicological outcomes associated with PSY were considered, regardless of exposure context, in order to reflect the current state of evidence. Results: The available evidence base is limited and heterogeneous, consisting primarily of case reports, observational data, and mechanistic preclinical studies. Reported adverse events are rare and frequently confounded by polysubstance use, uncertainty of dose, co-ingestion of other compounds, and lack of exposure standardization. Despite these limitations, biologically plausible mechanisms related to serotonergic receptor activation provide a rationale for further investigation of potential organ-specific effects. However, current controlled clinical data do not provide consistent evidence supporting intrinsic multi-organ toxicity of PSY. Conclusions: Current evidence does not confirm clinically meaningful intrinsic multi-organ toxicity of PSY under controlled conditions. Nevertheless, the available literature suggests the presence of potential safety signals that warrant further systematic evaluation. In the context of growing clinical interest in PSY, this review provides a structured synthesis of current knowledge and highlights critical gaps in understanding its organ-specific safety profile. Full article

Background: Major depressive disorder, particularly in its treatment-resistant form, remains a leading cause of global disability. When pharmacotherapy and psychotherapy fail, neuromodulation techniques such as electroconvulsive therapy (ECT) and repetitive transcranial magnetic stimulation (rTMS) are increasingly utilized. However, variability in protocols and outcome reporting continues to generate uncertainty regarding their comparative benefits and safety profiles. Objective: To comprehensively map and synthesize the available evidence on the clinical benefits and adverse effects of ECT and rTMS in adults with major depressive disorder and treatment-resistant depression. Methods: A scoping review was conducted following PRISMA-Sc guidelines and registered in PROSPERO; PubMed–MEDLINE, Scopus, and the Virtual Health Library were searched from inception to October 2022. Observational and experimental studies evaluating ECT and or rTMS in adults with depressive disorders were included. Data were extracted on study design, population characteristics, stimulation parameters, clinical outcomes, and adverse effects. Methodological quality was assessed using National Heart, Lung, and Blood Institute tools. Results: A total of 165 studies comprising 10,701 participants were included. ECT and rTMS were consistently associated with clinically meaningful reductions in depressive symptom severity across heterogeneous protocols. ECT demonstrated the most robust response rates, particularly in treatment-resistant and severe depression, while rTMS showed substantial efficacy with a more favorable safety profile. Adverse effects were more frequent and severe with ECT, including transient cognitive disturbances and cardiovascular complications, whereas rTMS was predominantly associated with mild, self-limited side effects such as headache and scalp discomfort. Considerable heterogeneity in stimulation parameters and diagnostic subgroups was observed across studies. Conclusions: Both ECT and rTMS represent effective neuromodulation strategies for major depressive disorder and treatment-resistant depression. ECT remains the most potent intervention in highly refractory cases, whereas rTMS offers a less invasive alternative with strong tolerability. Standardization of stimulation protocols, biomarker-informed stratification, coadjuvancy analysis, and long-term controlled studies are necessary to refine clinical positioning and advance precision neuromodulation in depression care. Full article

Background/Objectives: Electroconvulsive therapy (ECT) is among the most effective treatments for severe major depression, treatment-resistant depression, psychotic and bipolar depression, catatonia, and selected psychotic disorders. Yet response, remission, seizure adequacy, and cognitive tolerability remain difficult to predict for an individual patient. This review examines whether oral and gut microbial signatures can inform precision ECT as contextual biological markers, rather than as standalone explanations of ECT efficacy. Methods: A structured narrative PubMed/MEDLINE search was conducted on 1 May 2026 and supplemented by targeted manual searches of Crossref, Google Scholar, journal websites, and reference lists updated through 17 May 2026. Evidence was grouped as direct human ECT–microbiome studies, indirect human ECT biomarker studies, preclinical electroconvulsive shock (ECS) studies, and mechanistic microbiome–gut–brain literature. Results: Direct human ECT–microbiome evidence remains very limited and currently consists of two small prospective cohorts with sufficient microbiome data, totaling approximately 25 patients across studies, plus one single-patient case report. In severe or treatment-resistant depression, a pilot oral microbiome study with sufficient microbiological data from 14 patients reported higher pre-treatment oral alpha diversity in responders than in non-responders, without a consistent global oral microbiome shift after ECT. In schizophrenia, a small stool microbiome cohort of 11 patients suggested that baseline Bifidobacterium and Lactobacillus proportions may relate to symptom improvement, although sample size and confounding preclude firm inference. Conclusions: Microbiome-informed precision ECT remains a biologically plausible research direction, but current human evidence supports only cautious evaluation of baseline microbial context as a candidate predictor, not clinical microbiome-guided ECT, mediation, or microbiome-modifying intervention. The strongest current biological bridge comes from inflammatory markers, particularly baseline CRP and IL-6. Preclinical ECS studies support gut inflammatory, motility and vagal mechanisms, but they cannot substitute for human validation. Full article

Background: This systematic review and meta-analysis evaluates the efficacy and safety of psilocybin-assisted psychotherapy (PAP) for adults with major depressive disorder (MDD). Methods: A PROSPERO-registered search (CRD42024561979) of CENTRAL, Scopus, PsycINFO, and MEDLINE (2010–2024) identified clinical trials assessing PAP. Risk of bias was assessed using RoB 2 for randomized controlled trials (RCTs), while non-randomized studies were appraised separately. Evidence certainty was evaluated using GRADE. Results: Ten trials were included; eight provided quantitative data. PAP was associated with large short-term reductions in depressive symptom severity. The overall pooled effect was large (d = 1.15, 95% CI 0.83–1.48), though within-subject designs yielded larger estimates (d = 1.63) than between-subject controlled comparisons (d = 0.96). Adverse events were transient and manageable, with no increased risk of serious adverse events on dosing days. Primary risk-of-bias concerns included functional unblinding. Conclusions: PAP may produce clinically meaningful, large short-term reductions in depressive symptoms. However, long-term efficacy remains understudied, and the overall certainty of evidence is low to moderate. Larger, rigorously blinded trials are required. Full article

Background: Treatment-resistant depression (TRD) poses a major clinical challenge, particularly when accompanied by suicidal behavior. Intranasal esketamine has demonstrated rapid antidepressant effects in TRD, but real-world comparative evidence remains limited. Methods: We conducted a six-month naturalistic prospective cohort study in two Spanish mental health centers, including 62 TRD patients with high suicide risk undergoing fourth-line treatment. Thirty patients received intranasal esketamine and thirty-two alternative pharmacological interventions. Suicidal ideation (C-SSRS), depressive symptoms (HAM-D-17) and functional status (FAST) were assessed at baseline and at 1-, 3- and 6-month follow-ups. Results: Both groups showed significant improvement during follow-up; however, esketamine-treated patients exhibited a faster and greater reduction in suicidal ideation and depressive symptoms than those receiving alternative pharmacological strategies. The number needed to treat to prevent one case of high suicide risk was 1.35. Functional improvement was comparable between groups. Conclusions: In real-world clinical settings, intranasal esketamine was associated with a faster and greater reduction in suicidal ideation and depressive symptoms among TRD patients with high suicide risk, supporting its role as a rapid-acting therapeutic option within comprehensive and closely monitored care. Full article

Major depressive disorder (MDD) is a complex and heterogeneous psychiatric disorder with a high prevalence. Neuroinflammation may define biologically distinct patient subgroups with different mechanisms, clinical phenotypes, and treatment responses. This narrative review integrates current evidence around three linked questions: how neuroinflammatory processes contribute to depression, how biomarkers can identify clinically relevant inflammatory phenotypes, and how these findings can inform anti-inflammatory treatment strategies. The major mechanisms discussed include microglial activation and neuroimmune signaling, hypothalamic–pituitary–adrenal axis dysregulation and glucocorticoid receptor resistance, kynurenine pathway alterations, and cytokine-driven impairment of neurogenesis and synaptic plasticity. These pathways interact with stress responses, neurotransmitter systems, and neuronal function, while their expression may vary according to sex, age, hormonal status, disease stage, and treatment exposure. These interconnected pathways may contribute to depressive symptoms by disrupting neurotransmitter systems and impairing neural plasticity. In addition, this review discusses several candidate biomarkers, including C-reactive protein (CRP), interleukin-1β (IL-1β), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), brain-derived neurotrophic factor (BDNF) and transforming growth factor-β1 (TGF-β), which may support patient stratification, treatment prediction, and assessment of target engagement. Clinical trials of anti-inflammatory agents have shown inconsistent and generally modest effects in unselected MDD populations. By integrating mechanistic evidence with biomarker-guided therapeutic implications, this review aims to clarify how neuroinflammatory research may inform more precise and individualized treatment strategies for depression. Full article

Background/Objectives: Treatment-resistant depression (TRD) remains one of the most urgent unmet needs in psychiatry, while its therapeutic pipeline is evolving rapidly. To characterize current development trajectories, we conducted a registry-anchored mapping of interventional trials in adults with major depressive disorder and treatment resistance (MDD-TRD), with the aim of defining the distribution of intervention types, endpoint choices, and key design features across the active trial landscape. Methods: We systematically searched ClinicalTrials.gov, the EU Clinical Trials Information System, and ISRCTN for interventional MDD-TRD trials registered up to 18 September 2025. After data cleaning and cross-registry deduplication, 237 unique trials were retained. Interventions were categorized through a taxonomy distinguishing device-based neuromodulation, pharmacological strategies, biologic/novel agents, multimodal non-digital combinations, digital–hybrid programs, psychotherapy, and lifestyle interventions, with classification anchored on structured registry intervention tags and whole-word matching across title and intervention text. Primary endpoints were flagged as standard when they explicitly referenced the Montgomery–Åsberg Depression Rating Scale or Hamilton Depression Rating Scale. We also examined developmental phase, sample size, and recurrent methodological features. Results: Device-based neuromodulation accounted for the largest share of the active pipeline (114/237, 48.1%), followed by pharmacological strategies (86/237, 36.3%), biologic/novel agents (16/237, 6.8%), and multimodal non-digital combinations (11/237, 4.6%). Digital–hybrid programs represented a small but distinctive stratum (5/237, 2.1%), with the remaining records comprising lifestyle interventions (3/237, 1.3%) and psychotherapy (2/237, 0.8%). Standard clinician-rated primary endpoints were used in 63.3% of studies. Trial development was concentrated in mid-phase designs, whereas sample sizes were generally modest (median 49; interquartile range, 19–87). Across modalities, increasing attention was directed to durability of response, functioning, and patient-reported outcomes, with adaptive and enrichment-based designs appearing with greater frequency. Conclusions: The contemporary TRD trial ecosystem is structured around two co-active developmental tracks—device-based neuromodulation and pharmacology with novel mechanisms—accompanied by a smaller but measurably expanding biologic/novel stratum and a still-marginal digital–hybrid presence. This registry-based mapping provides a near-real-time overview of the field and may support future harmonization of trial endpoints and design standards. 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

Background: Treatment-resistant depression (TRD) represents a major clinical challenge and is increasingly associated with persistent neuroinflammatory processes. Evidence suggests that dysregulation of the immune system, particularly the imbalance between pro-inflammatory and anti-inflammatory cytokines, contributes to poor therapeutic response. In this context, interleukin-10 (IL-10) has emerged as a key mediator in regulating the inflammatory response. Objective: To systematically analyze the evidence on neuroimmune dysregulation in depression, with an emphasis on TRD, and to evaluate the potential role of IL-10 as a biomarker and modulator of therapeutic response. Methods: A systematic review was conducted in accordance with PRISMA guidelines. Fourteen studies were included, comprising randomized clinical trials, longitudinal studies, a prospective cohort study, and exploratory designs. Methodological quality was assessed using the RoB 2 tool and complementary approaches. Data were integrated through a qualitative analysis focused on inflammatory biomarkers and clinical outcomes. Results: The studies consistently showed an association between elevated levels of pro-inflammatory cytokines, such as IL-6 and TNF-α, and the severity of depressive symptoms, as well as reduced response to conventional treatments. Immunomodulatory interventions, including ketamine, pentoxifylline, and minocycline, were associated with clinical improvement, particularly in patients with elevated baseline inflammation. IL-10 appears to be involved in counter-regulatory neuroimmune processes associated with inflammatory balance. Conclusions: Neuroinflammation plays a central role in TRD. IL-10 may serve as a relevant biomarker and a potential target for personalized therapeutic strategies informed by immune profiles, through modulation of neuroinflammatory pathways. Full article