Search Results (471)

Abnormal activation of endoplasmic reticulum stress (ERS) is an important driving factor for the occurrence and development of depression. As a safe and effective non-drug intervention, exercise plays an important role in improving depression-like behavior. This paper systematically reviews the core role of ERS-mediated neuronal apoptosis, inflammatory response, calcium homeostasis imbalance and autophagy abnormalities in depression and focuses on the molecular mechanism of exercise to improve depression by regulating ERS and its downstream signals. Existing evidence shows that exercise can exert antidepressant effects through multi-level remodeling of ERS-related signaling networks, including inhibiting UPR-related apoptosis, inhibiting microglial pro-inflammatory polarization, regulating MAMs-mediated calcium-mitochondrial interaction, and restoring autophagy activity (LC3-II, Beclin-1). Although the above findings provide a new potential perspective for explaining the antidepressant effect of exercise, its precise intervention application is still limited by the lack of population research, unclear selection of exercise types and large differences in exercise intensity. This article aims to review and analyze the mechanism of endoplasmic reticulum stress in the improvement of depression by exercise, in order to provide a new theoretical reference for the prevention and treatment of depression. Full article

Background/Objectives: Vestibular migraine is a common but often underrecognized cause of dizziness in otolaryngology practice. Although awareness has increased, variation in clinician training and management may contribute to inconsistent care. This study evaluated current diagnostic and treatment practices of Canadian otolaryngologists for vestibular migraine, including familiarity with diagnostic criteria, therapeutic approaches, perceived barriers, and educational needs. Methods: A national cross-sectional electronic survey was distributed to practicing and emeritus members of the Canadian Society of Otolaryngology–Head and Neck Surgery from February to April 2025. The 14-item survey assessed demographics, clinical exposure to dizzy patients, residency training, diagnostic familiarity, treatment patterns, referral practices, barriers to care, and preferred educational resources. Responses were anonymized and analyzed using descriptive statistics. Results: Forty-four otolaryngologists completed the survey (response rate: 7.4%). Most respondents reported being very familiar (59.1%) or moderately familiar (38.6%) with vestibular migraine diagnostic criteria, and 97.7% reported currently diagnosing and/or treating these patients. However, only 15.9% had received extensive residency training specific to migraine or vestibular migraine. Common treatments included lifestyle and dietary modification (90.9%), nutraceutical supplements (59.1%), tricyclic antidepressants (54.5%), and analgesics (52.3%). Vestibular rehabilitation therapy (29.5%) and calcitonin gene-related peptide-targeted therapies (<10%) were used less frequently. Major barriers were clinical time constraints (65.9%), lack of training or knowledge (54.5%), and diagnostic complexity (47.7%). Clinical guidelines (70.5%) and continuing medical education courses (65.9%) were identified as the most valuable supports. Conclusions: Among surveyed Canadian otolaryngologists engaged in dizziness and vestibular migraine care, substantial heterogeneity existed in training and management practices. Standardized guidance, enhanced education, and interdisciplinary collaboration may improve consistency of care and patient outcomes. 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: A significant percentage of patients with major depressive disorder (MDD) fail to achieve remission with antidepressant monotherapy and frequently experience residual mood and cognitive symptoms that impair their functional recovery. Thus, an augmentation with vortioxetine, a multimodal antidepressant with reported cognitive benefits, might be a useful strategy for such patients. Methods: We conducted a 12-week naturalistic, prospective observational study in a Malaysian university hospital; 40 adults with MDD and inadequate response to at least eight weeks of antidepressant therapy received either adjunctive vortioxetine or optimization of their existing antidepressant as part of treatment-as-usual care. Depressive symptoms were assessed using the Montgomery–Åsberg Depression Rating Scale (MADRS), cognitive symptoms using the Perceived Deficits Questionnaire-5 (PDQ-D5), and global improvement using the Clinical Global Impressions—Improvement (CGI-I) scale. Results: Both groups demonstrated significant improvements in MADRS and PDQ-D5 scores over 12 weeks (p < 0.001). Remission rates at Week 12 were high in both groups (93.8% adjunctive vortioxetine vs. 86.7% control). Both groups demonstrated significant improvements in depressive and cognitive symptoms over 12 weeks. Although between-group differences were not statistically significant, descriptive trends toward earlier symptomatic improvement were observed in the adjunctive vortioxetine group in several core depressive symptoms, including apparent sadness, suicidal ideation, and appetite disturbance. Greater clinician-rated global improvement was observed in the vortioxetine group at Week 12 (87.5% vs. 40.0%, p < 0.001). Conclusions: In this outpatient clinical setting, adjunctive vortioxetine was associated with earlier improvement of core depressive symptoms and greater global clinical improvement compared with optimization of existing antidepressant therapy. Collectively, these findings suggest adjunctive vortioxetine as a clinically relevant option for patients with MDD who show an inadequate response to antidepressant monotherapy; however, findings are exploratory and not causal, and thus larger RCTs are needed for affirmation. Full article

Pharmacotherapy of neuropathic pain (NP) remains challenging due to its heterogeneous etiology, lack of objective diagnostic tools, and the limited efficacy of currently available treatments, including antidepressants, anticonvulsants, and local anesthetics. Therefore, the search for novel therapies with improved analgesic efficacy and reduced adverse effects is of growing importance. In this context, natural alkaloids have emerged as promising candidates, demonstrating analgesic potential in both diabetes-induced neuropathy and various experimental models of NP. This review outlines NP pathophysiology, emphasizing maladaptive changes within the somatosensory nervous system, including peripheral and central sensitization, as well as glial cell activation. Furthermore, it discusses the mechanisms through which alkaloids may modulate NP-related pathways, with particular focus on their interactions with ion channels, signaling pathways, inflammatory responses, and oxidative stress. A literature search was conducted using the Scopus, Google Scholar and PubMed databases for papers published between 2015 and 2026, using the keywords “alkaloids” and “neuropathic pain”, and focused on recent findings regarding the antinociceptive effects of berbamine, tetrandrine, fangchinoline, and sinomenine, and their derivatives. The analysis indicates that, despite promising preclinical evidence, further rigorous preclinical and clinical studies are necessary to fully assess their therapeutic potential in the treatment of NP. Full article

Background and Objectives: Treatment-resistant depression (TRD) is a major clinical challenge in the management of major depressive disorder (MDD). While pharmacogenetics has been suggested to be clinically useful in guiding antidepressant treatment, few studies have explored if and how pharmacogenes can be involved in TRD pathophysiology and its clinical outcomes. Material amd Methods: We explored the role of differences in metabolizer phenotypes, gene expression levels, and microRNAs of three key pharmacogenes (CYP2D6, CYP2C19, CYP2B6) in TRD pathophysiology and antidepressant response in a cohort of 300 patients with MDD from the PROMPT consortium. Results: CYP2D6 phenotype distribution did not differ significantly between TRD and non-TRD groups, but mRNA expression was significantly upregulated in TRD. Hsa-miR-26b-5p, a microRNA predicted to regulate CYP2D6, was significantly downregulated in TRD. For CYP2C19, intermediate metabolizers (IMs) were underrepresented in TRD versus non-TRD (IMs vs. normal metabolizers (NMs): χ² = 6.07, p = 0.019). microRNA hsa-let-7d-5p and hsa-miR-27a-3p, predicted to regulate CYP2C19, were significantly downregulated in TRD. No significant differences were found for CYP2B6. Conclusions: This study contributes valuable insights to the PROMPT project on how pharmacokinetic gene variants and their expression and regulatory mechanisms may influence antidepressant response and resistance in MDD. Full article

Background: Research indicates that hepatic gluconeogenesis mediates metabolic coupling between the liver and muscles via the Cori cycle and participates in liver–brain axis communication through its metabolic products and regulatory networks, thereby linking it to the pathogenesis of depression. Together, these mechanisms form the molecular basis for the antidepressant effects of exercise-regulated hepatic gluconeogenesis. Regular exercise promotes skeletal muscle contraction, causing the muscles to release more lactate into the circulatory system. Lactate acts as a substrate for gluconeogenesis and activates downstream signaling pathways, thereby enhancing the gluconeogenic response. During exercise, glycogenolysis directly provides energy, while lactate produced by glycolysis enters the liver via the Cori cycle to serve as a substrate for gluconeogenesis. By maintaining blood glucose homeostasis, this process ensures a stable energy supply to the brain, thereby improving cognitive and emotional functions. This study aims to elucidate how key substrates, regulatory factors, and rate-limiting enzymes involved in hepatic gluconeogenesis and exercise influence brain energy supply, cognitive function, and emotional regulation during depression. It seeks to identify the potential targets and mechanisms through which exercise exerts its antidepressant effects via hepatic gluconeogenesis, with the goal of providing a theoretical foundation for research into the mechanisms of depression and for clinical exercise interventions. Methods: This review conducted a comprehensive search of the recent literature on exercise, hepatic gluconeogenesis, and depression in major domestic and international databases. Adopting an interdisciplinary approach that integrates hepatic gluconeogenesis and exercise, it synthesizes existing evidence to explore the metabolic mechanisms by which exercise improves depression through the regulation of hepatic gluconeogenesis pathways. Results: Research has found that exercise may modulate hepatic gluconeogenic substrates and regulate the expression of cAMP-responsive element-binding protein in states of depression, regulatory factors such as liver kinase B1, forkhead box protein 01, hepatocyte nuclear factor 4 alpha, and peroxisome proliferator activated receptor gamma co activator factor 1 alpha are used to affect key rate limiting enzymes of hepatic gluconeogenesis, such as phosphoenolpyruvate carboxykinase and glucose-6-phosphatase, enhance hepatic gluconeogenesis processes, maintain blood glucose homeostasis, ensure brain energy supply, and improve depression. Conclusions: Exercise intervention targeting hepatic gluconeogenesis may be a potential therapeutic strategy for depression. Full article

Depression is a highly heterogeneous psychiatric disorder with its pathogenesis increasingly linked to dysregulated neuroinflammation. Microglia, as the resident immune cells of the central nervous system (CNS), play a pivotal role in the initiation and progression of the neuroinflammation and the pathophysiology of depression. These cells exhibit a dual role in pro- and anti-inflammatory processes, dynamically regulating immune responses through immunometabolic reprogramming in response to environmental cues. This review elaborates how metabolic remodeling in microglia, particularly within glucose, lipid, and amino acid pathways, drives their polarization toward a pro-inflammatory phenotype. This shift promotes depression pathogenesis via the release of inflammatory factors, disruption of synaptic plasticity, and mediation of neurotoxicity. We further discuss the impact of existing antidepressants on cellular metabolism and highlight the promise and challenges of targeting specific microglial metabolic pathways as a novel therapeutic strategy. This synthesis provides new insights into the immunometabolic mechanisms of depression and outlines directions for developing targeted treatments. Full article

Background/Objectives: Major depressive disorder (MDD) remains a leading cause of disability worldwide and exhibits substantial biological heterogeneity that is not adequately captured by current symptom-based diagnostic systems. While the classical monoamine hypothesis has historically guided antidepressant development, it does not fully account for variability in treatment response, delayed therapeutic onset, or the persistence of cognitive and anhedonic symptoms. Converging evidence from molecular, neuroimaging, and translational studies increasingly implicates glutamatergic dysregulation and impaired neuroplasticity as key mechanisms in depressive pathology. This narrative review aims to integrate monoaminergic and glutamatergic perspectives within a dimensional framework that may help explain clinical heterogeneity and inform mechanism-based treatment strategies. Methods: A narrative synthesis of the literature was conducted using major biomedical databases including PubMed, Scopus, and Web of Science. Preclinical studies, neuroimaging investigations, biomarker research, randomized clinical trials, and meta-analyses examining monoaminergic dysfunction, glutamatergic signaling, neuroplasticity pathways, and rapid-acting antidepressants were reviewed and thematically integrated. Results: Evidence indicates that depressive syndromes may reflect varying contributions of monoaminergic dysregulation and glutamatergic–neuroplastic impairment. Monoaminergic disturbances interact with inflammatory and neuroendocrine processes, including cytokine-driven activation of the kynurenine pathway. In parallel, alterations in glutamatergic signaling, glial function, and BDNF–TrkB–mTOR pathways contribute to synaptic atrophy and network dysfunction. Rapid-acting antidepressants such as ketamine, esketamine, and dextromethorphan–bupropion provide clinical proof-of-concept that direct engagement of synaptic plasticity mechanisms can accelerate symptom improvement, particularly in treatment-resistant depression. Conclusions: Integrating monoaminergic and glutamatergic mechanisms within a “monoamine–glutamate continuum” offers a conceptual framework for understanding depressive heterogeneity and treatment response. Multimodal approaches combining clinical phenotyping with inflammatory, neuroimaging, and molecular markers may ultimately support mechanism-informed precision psychiatry strategies in major depressive disorder. Full article

(1) Different classes of antidepressant drugs have been shown to activate lysophosphatidic acid (LPA) receptors, but their effects on the receptor signaling stimulated by LPA have not been fully investigated. In the present study, we examined the effect of the tricyclic antidepressant amitriptyline on the LPA-induced activation of extracellular signal-regulated kinases 1 and 2 (ERK1/2) and Rho signaling in C6 glioma cells and cultured rat astrocytes. (2) LPA receptor signaling was investigated by using Western blot and microscopic immunofluorescence assays. Rho activation was determined by a pull-down assay. (3) Amitriptyline potentiated the LPA-induced activation of ERK1/2 signaling, as indicated by the more than additive increases in the phosphorylation/activation of key components of this pathway including fibroblast growth factor 1 receptor, MEK1/2, ERK1/2, Elk-1, and cyclic AMP response element binding protein (CREB). Amitriptyline also enhanced the expression of brain-derived neurotrophic factor (BDNF) elicited by LPA. In contrast, the antidepressant failed to mimic the LPA-induced activation of Rho and Rho-dependent responses, such as the reversal of astrocyte stellation, accumulation of stress fibers, and the phosphorylation of focal adhesion kinase and myosin target subunit of myosin phosphatase isoform 1. Moreover, when combined with LPA, amitriptyline curtailed Rho activation and the Rho-mediated cellular responses. (4) These results demonstrate that in astroglial cells, amitriptyline exerts a balanced action on LPA-activated receptors by enhancing the neuroprotective ERK1/2-CREB-BDNF signaling and dampening the potentially detrimental Rho–ROCK pathway, and suggest that this unique property may contribute to the antidepressant activity of the drug. Full article

Introduction: Major Depressive Disorder (MDD) has been increasingly associated with inflammatory dysregulation, particularly involving tumor necrosis factor-alpha (TNF-α). Genetic polymorphisms within the TNFA promoter region have been investigated as potential modulators of depressive susceptibility, symptom expression, treatment response, and inflammatory comorbidity. However, findings remain inconsistent across populations and clinical contexts. Methods: This systematic review adhered to PRISMA 2020 guidelines and was registered in PROSPERO (CRD420251242724). Observational and interventional studies evaluating associations between TNFA polymorphisms—specifically rs1800629 (−308 G/A), rs1799724 (−857 C/T), and rs1799964 (−1031 T/C)—and MDD-related outcomes in adults were included. Data extraction and methodological quality assessment were performed independently using an adapted GRIPS framework. Results: Eleven studies met the inclusion criteria, with eight investigating MDD without cardiovascular comorbidity and three assessing cardiovascular populations. Across diverse cohorts, rs1800629 and rs1799724 did not demonstrate consistent associations with MDD susceptibility. Although isolated population-specific findings were reported, genotype and allele distributions were generally comparable between cases and controls. Rs1799724 was associated with symptom dimensions and altered TNF-α expression in two cohorts. Rs1799964 was not linked to disease occurrence but showed potential association with antidepressant response and adverse cardiovascular outcomes in patients with chronic heart failure and comorbid depression. Overall, findings were heterogeneous and influenced by population characteristics, sample size, and clinical context. Conclusions: Current evidence does not support a robust etiological role for TNFA promoter polymorphisms in major depressive disorder. These variants may exert context-dependent modulatory effects on symptom expression, treatment response, or inflammatory-cardiovascular interactions rather than serving as primary susceptibility determinants. Larger, ethnically diverse studies integrating genetic, inflammatory, and clinical data are required to clarify the contribution of inflammatory genetic variability in depressive disorders. Full article

Background/Objectives: Burning mouth syndrome (BMS) is a chronic idiopathic orofacial pain disorder characterized by persistent intraoral burning in the absence of detectable mucosal alterations. Diagnosis is challenging due to the lack of specific biomarkers and the need to exclude numerous systemic and local conditions that can mimic oral burning. This literature review aims to summarize current and emerging therapeutic strategies for BMS. Methods: A structured and filtered search of PubMed, Scopus, and Web of Science identified studies evaluating pharmacological, phytotherapeutic, and non-pharmacological interventions. Results: Various antidepressants, anticonvulsants, benzodiazepines, H2 receptor antagonists, and low-dose naltrexone have demonstrated varying degrees of symptom reduction, while alpha lipoic acid (ALA) and phytomedicines such as capsaicin, Hypericum perforatum, Catuama, lycopene, crocin, and melatonin show mixed clinical benefits. Non-pharmacological approaches, including photobiomodulation (PBM), oral cryotherapy, neuromodulation techniques, and cognitive behavioral therapy, also provide meaningful symptom improvement in many patients. Conclusions: Across all modalities, therapeutic responses remain heterogeneous and generally incomplete, underscoring the absence of a universally effective treatment. Current evidence supports an individualized and multidisciplinary approach that integrates pharmacological, psychological, and adjunctive therapies to address the multifactorial nature of BMS. Full article

Serotonin is a critical morphogen in early development, yet the mechanisms regulating its homeostasis in the preimplantation embryo remain unclear, particularly under conditions of maternal antidepressant exposure. Here, we investigated embryonic serotonergic autonomy using mouse models of pharmacological transport blockade (maternal fluoxetine treatment) and in vitro treatment with the monoamine oxidase inhibitor pargyline. We employed immunofluorescence, RT-qPCR, and live-cell imaging to assess metabolic flux, gene expression, and physiological health. We demonstrate that monoamine oxidase functions as a metabolic firewall, progressively maturing from zygote to blastocyst to degrade excess amines. Paradoxically, maternal serotonin transporter blockade triggered significant intracellular serotonin hyper-accumulation in blastocysts, associated with a trend toward a compensatory upregulation of the biosynthetic gene Ddc. While this serotonin overload did not compromise morphology, mitochondrial function, or pluripotency marker expression, it induced a robust epigenetic response. Excess serotonin promoted elevated H3Q5ser immunoreactivity in both nuclear and cytoplasmic compartments via a transglutaminase-dependent mechanism. These findings reveal that the preimplantation embryo possesses a resilient, autonomous serotonergic system capable of compensatory synthesis. However, environmental fluctuations are chemically recorded via transglutaminase-mediated serotonylation, representing an epigenetic mark that warrants further long-term study within the Developmental Origins of Health and Disease (DOHaD) framework. Full article

The role of the endocannabinoid system (ECS) in the development of depression and anxiety is being actively studied, with evidence suggesting that elevation of ECS signaling can have anxiolytic and antidepressant properties. The current study explored the therapeutic potential of Oleoyl Serine (OS), an endocannabinoid-like lipid, and HU-910, a synthetic selective Cannabinoid type 2 (CB2) receptors agonist, in depression and anxiety, using both sexes of the depressive-like genetic model: Wistar Kyoto (WKY) rats. The aim was to investigate behavioral and molecular mechanisms associated with acute and sub-chronic intraperitoneal administration of these compounds. We showed that, in females, acutely administered OS yielded antidepressant-like and anxiolytic-like effects in the Forced Swim Test (FST) and Open Field Test (OFT), respectively. In males, OS yielded acute and sub-chronic anxiolytic-like effects. HU-910 yielded an acute anxiolytic-like effect in females and an acute antidepressant-like effect in males. Sub-chronic administration of imipramine (IMI), used as a positive control, yielded an antidepressant-like effect in both sexes but an anxiogenic-like effect in females. Sub-chronic administration of all the treatments increased hippocampal Cannabinoid Receptor 1 (CNR1) mRNA expression (but not Fatty Acid Amide Hydrolase (FAAH)) in males. Exploratory in silico absorption, distribution, metabolism, and excretion (ADME) profiling suggests that sex-dependent pharmacokinetic variability may partly underlie the observed behavioral differences, in addition to possible pharmacodynamic factors. Our study provides a lead towards unraveling the putative sex differences in response to both conventional antidepressants (e.g., IMI) and emerging pharmacological agents (e.g., OS, HU-910). Further, our study helps advance the field of neuropharmacology by elucidating the anxiolytic-like and antidepressant-like effects of OS and HU-910. Full article

Background/Objectives: Psilocybin has re-emerged as a promising intervention for neuropsychiatric disorders including major depressive disorder, treatment-resistant depression, anxiety associated with life-threatening illness, obsessive compulsive disorder, and substance use disorders. However, conventional randomized controlled trials (RCTs)—the current gold standard in evidence-based medicine—may not adequately capture the therapeutic complexity of psilocybin, which depends not only on pharmacological action but also on contextual, psychological, and interpersonal factors. This critical narrative review aimed to evaluate the adequacy of existing clinical research frameworks for assessing psilocybin’s therapeutic potential and to explore alternative methodologies that may better reflect real-world clinical conditions. Methods: Using the Web of Science Core Collection database, we identified and analysed the ten most cited clinical studies on psilocybin published between 2015 and 2025 inclusive. Additional literature was included through reference cross-checking, systematic reviews, meta-analyses, and interdisciplinary sources covering neurobiology, history, and real-world evidence (RWE). The review synthesizes clinical outcomes, methodological constraints, and epistemic considerations relevant to psychedelic-assisted therapy. Results: Evidence from highly cited trials demonstrates rapid and sustained antidepressant and anxiolytic effects of psilocybin, with notable benefits also observed in addiction treatment. However, significant methodological limitations were identified, including selection bias, challenges in placebo design and blinding, small sample sizes, and the underrepresentation of diverse populations. Psilocybin outcomes were strongly influenced by subjective experience and contextual factors such as set and setting. Emerging RWE studies revealed heterogeneous patterns of response and provided insights unattainable through RCTs alone. Conclusions: Psilocybin shows considerable therapeutic promise, but current RCT methodologies capture only part of its clinical effects. Comprehensive evaluation will require larger and more diverse clinical trials, long-term follow-up, standardized psychotherapeutic protocols, and the integration of RWE to reflect real-world practice. Psychedelic-assisted therapy should be conceptualized as a complex intervention that combines pharmacological and psychotherapeutic components. Full article