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This research investigated the potential therapeutic role of α-(phenylselanyl) acetophenone (PSAP) in the comorbidity of chronic pain and depression triggered by partial sciatic nerve ligation (PSNL). Male Swiss mice underwent PSNL surgery, and after a four-week period, they received either PSAP (1-50 mg/kg, administered intragastrically) or imipramine (IMI) (50 mg/kg) 30 min prior to behavioral assessments. Both PSAP and IMI effectively alleviated PSNL-induced hypersensitivity to pain and depressive-like symptoms, as demonstrated in forced swim and allodynia tests. Additionally, PSAP counteracted the elevated levels of lipid peroxidation and reactive oxygen species observed in the cortex and hippocampus following PSNL. These neuroprotective effects appear to be linked to PSAP's anti-inflammatory properties, as it downregulated the expression of pro-inflammatory markers such as NF-κB p65, TNF-α, and IDO mRNA in the affected brain regions. Furthermore, PSAP restored hippocampal BDNF mRNA levels, which had been diminished by nerve injury. Since inflammation is a common pathway in both chronic pain and depression, the findings indicate that PSAP holds promise as a treatment for this comorbid condition. Show less

Retigabine (RTG) shows notable neuroprotective efficacy in multiple brain injury models; however, its interplay with endoplasmic reticulum stress (ERS) is poorly understood. This study was designed to explore the therapeutic potential of RTG against CRS-induced depression-like behaviors and cognitive deficits in mice and to uncover the associated molecular mechanisms. A depression-like and cognitive impairment model was established in C57BL/6 male mice using chronic restraint stress (CRS). Six-week-old C57BL/6 male mice were randomly assigned to the following groups: control (Con), model (CRS), RTG (10 mg/kg), XE-991 (2 mg/kg) or tunicamycin (Tm, 2 mg/kg). Behavioral tests were conducted to assess depression-like behaviors and cognitive function. Hippocampal neuronal morphology was examined by H&E and immunofluorescence staining, while changes in endoplasmic reticulum stress (ERS)-related signaling pathways were analyzed by Western blot. Retigabine treatment reduced hippocampal neuronal damage and the expression of ERS-related factors (GRP78, CHOP) and the pro-apoptotic factor BAX in CRS-induced mice, while it increased the levels of BDNF. These effects were antagonized by XE-991 and the ERS agonist tunicamycin (Tm). Retigabine may alleviate CRS-induced depressive-like behaviors and cognitive impairment by inhibiting ERS-mediated apoptosis, suggesting its potential as a novel therapeutic strategy for depression. Show less

Sepsis elevates the risk of depression and cognitive impairment. Glucagon-like peptide-1 (GLP-1) analogues exhibit neuroprotective potential, yet their effects on sepsis-induced depression (SID) remain unelucidated. This study explored whether exenatide (Exe) alleviates depressive-like behaviors and cognitive deficits in a murine SID model. SID mice were intraperitoneally administered exenatide (1 mg/kg/day) or vehicle for 14 days. Behavioral assessments included the Open Field Test, Forced Swimming Test, Tail Suspension Test, Sucrose Preference Test, Morris Water Maze, Novel Object Recognition, Novel Location Recognition, Three-Chamber Social Interaction Test, and IntelliCage system. Murine sepsis clinical scores and Nissl staining evaluated the model behaviorally and histologically. High-performance liquid chromatography quantified hippocampal 5-hydroxytryptamine (5-HT) and dopamine (DA), while enzyme-linked immunosorbent assay measured hippocampal and plasma biomarkers. Chronic exenatide treatment significantly reduced immobility time in the Forced Swimming and Tail Suspension Tests, improved cognitive performance in the Morris Water Maze, enhanced sucrose preference, and boosted novel object/location recognition and social interaction. Exenatide downregulated tumor necrosis factor-α, interleukin-6, and adrenocorticotropic hormone levels, while upregulating 5-HT, DA, phosphorylated cAMP response element-binding protein, and brain-derived neurotrophic factor. Exenatide exerts antidepressant-like and pro-cognitive effects in SID mice, likely via GLP-1 receptor-mediated suppression of hippocampal inflammation and promotion of neuroplasticity. GLP-1 analogues are promising dual-action therapeutics for comorbid depression and cognitive deficits, pending validation in further models and clinical trials. Show less

Non-small cell lung cancer (NSCLC) is characterized by high morbidity and lethality, causing a great physical and psychological burden on patients. Therefore, effective treatment of NSCLC patients is very important. This study analyzes the impact of a nursing intervention of case management combined with cognitive-behavioral therapy on anxiety and depression and quality of life in postoperative NSCLC patients. A single-center, non-randomized controlled study in which 80 NSCLC patients from the Hospital were enrolled from May 2023 to January 2024, and were categorized into case management (CM) and cognitive-behavioral therapy (CBT) groups depending on treatment modalities, with case management care in both groups, and cognitive-behavioral therapy care added to the CM combined with CBT (CC) group. The Hamilton anxiety scale (HAMA), Hamilton depression scale (HAMD), self-perception burden scale (SPBS), life qualities (QLQ-C30), neurotransmitter levels, and clinical effectiveness were primarily assessed in both groups post-treatment. Secondary outcomes included pain level (VAS score), nursing satisfaction, adverse events, and complications. After treatment, the indicators of both groups were significantly different from those of the pre-treatment. Post-treatment, the CC group demonstrated significantly lower scores than the CM group in HAMA (10.18 ± 2.10 vs. 16.04 ± 3.89), HAMD (11.94 ± 2.91 vs. 16.81 ± 3.19), and SPBS (25.52 ± 3.17 vs. 33.50 ± 5.61) (all P < 0.05). Conversely, the CC group showed significantly higher QLQ-C30 scores and levels of 5-hydroxytryptamine (5-HT) and brain-derived neurotrophic factor (BDNF). The nursing intervention of case management combined with cognitive behavioral therapy has a good improvement effect on the anxiety and depression status of NSCLC patients. It can improve the quality of life, which is worth promoting and using in the clinic. Show less

This study aimed to investigate changes in brain structure and function of hippocampus in aged type 2 diabetes mellitus (T2DM) rats and the effects of tea polyphenol (TP) intervention using magnetic resonance imaging (MRI) and tissue-level molecular analyses. Rats were randomly assigned to six groups: Control, Aged, Aged T2DM, Aged T2DM + TP, Aged T2DM + rosiglitazone, and Aged T2DM + piracetam intervention groups. Anxiety- and depression-like behaviors were assessed using the open field test, the forced swimming test and elevated plus maze. Brain structure, blood flow and neuro-associated metabolites were evaluated via MRI. The number of nerve cells, neurons, microglia and astrocytes, the expression of BDNF/CREB/p-CREB protein, the levels of inflammatory factors, and the integrity of the myelin sheath in the hippocampus were evaluated. Relationships between behavioral, cellular and molecular changes and MRI-derived indicators were evaluated by Pearson correlation analysis. Aged T2DM rats exhibited severe anxiety- and depression-like behaviors accompanied by brain atrophy, reduced blood flow and decreased brain metabolites. At the microstructural level, the number of hippocampal neurons in the Aged T2DM group was significantly reduced, accompanied by increased counts of microglia and astrocytes. Meanwhile, the expression levels of hippocampal p-CREB and BDNF were decreased, the concentration of the inflammatory factor IL-1β, IL-6, TNF-α was elevated, and myelin integrity was impaired. Intervention with TP alleviated anxiety- and depression-like behavior, with MRI-detected abnormalities and in vitro histopathological molecular changes improved (except for myelin integrity). TP intervention mitigated alterations in brain structure and function as well as anxiety and depression-like behaviors in aged T2DM rats. Show less

We aim to verify clinical (depressive symptoms, rates of psychiatric admissions, and suicide attempts) and neurobiological (Brain-Derived Neurotrophic Factor - BDNF) changes in outpatients with depression undergoing evidence-based psychotherapies (EBP) over a 6-month follow-up. Longitudinal, naturalistic, prospective study, with 47 outpatients undergoing EBP, and 48 healthy controls (HC) for the BDNF levels comparisons. Data were collected at baseline and 6-month follow-up. Statistical analysis was performed using a paired t-test and a multiple linear regression model. BDI scores did not differ between baseline and 6-month follow-up (p = 0.253), and the rates of hospitalizations and suicide attempts at 6-month follow-up were 4.2% (2 cases reported). All patients were using psychotropics. BDNF levels at baseline and after 6-month follow-up did not vary significantly in the patient group (p = 0.314). There was no difference between patients' BDNF levels at baseline and HC BDNF levels (p = 0.211) and between patients' BDNF levels at 6-month follow-up and HC BDNF levels (p = 0.772). Using a mood stabilizer increased the BDNF levels. BDNF levels remained stable. Adding psychotherapy to medication may be associated with low rates of suicide attempts and psychiatric admissions in our sample. Our findings reinforce the importance of combined treatment in preventing adverse outcomes in naturalistic settings. Evidence supports the clinical effectiveness and economic efficiency of psychotherapy for patients with mental disorders, suggesting that outpatient psychotherapy can benefit healthcare systems and patients. Our findings corroborate the literature and reinforce the importance of psychotherapy associated with pharmacotherapy (combined treatment) to prevent outcomes such as further hospitalizations and suicide attempts, even in individuals with a history of severe psychiatric conditions. Research on how psychotherapy works, in terms of psychological mechanisms and its underlying effects on biological processes, is crucial. Scientific evidence makes it possible to include psychotherapies in public health policies worldwide, benefiting individuals suffering from mental disorders. Evidence from naturalistic designs is scarce in the literature. Show less

Chronic pain (CP) and major depressive disorder (MDD) are highly disabling global diseases, and their high comorbidity creates a bidirectional vicious cycle, significantly exacerbating functional impairment and treatment resistance. Multidisciplinary evidence suggests that the comorbid nature arises from deep functional coupling and neural network remodeling between the sensory-pain and emotional systems, rather than merely a symptom overlap. Neuroimaging, animal models, and neuromodulation studies demonstrate that key brain regions, including the prefrontal cortex (PFC), anterior cingulate cortex (ACC), amygdala, hippocampus, insula, and reward system, show consistent abnormalities in the comorbid state, creating a cross-brain network that jointly regulates pain, emotion, and cognition. This paper systematically reviews the central structures, neural circuits, and neurotransmitter regulatory mechanisms of CP-MDD comorbidity and proposes an integrated emotion-perception coupling network model. We highlight the mechanisms and translational potential of multi-pathway intervention strategies, with a focus on neuromodulation techniques (rTMS, tDCS), combined with ketamine, BDNF modulators, and anti-inflammatory drugs. Additionally, it is emphasized that future research must integrate multimodal imaging, multi-omics data, and computational modeling to establish a mechanism-driven personalized stratification system. With the support of high spatiotemporal resolution brain connectomics technology, this will facilitate the transition from a 'symptom control' to a 'mechanism repair' paradigm in treating comorbidities. Show less

Formononetin (FMN) is known for its significant neuroprotective effects, this study aims to investigate the antidepressant potential and underlying mechanisms of FMN. Antidepressant efficacy was evaluated in corticosterone (CORT)-induced depression models. In vivo, CORT-exposed mice received FMN to assess behavioral and hippocampal changes (dendritic spine density, synaptic markers: MAP-2/GAP-43). In silico, network pharmacology and molecular docking predicted FMN's binding affinity and enriched pathways. In vitro, HT22 cells pretreated with FMN (10 μM, 6 h) were subjected to CORT injury, with mechanistic validation via ERα antagonist (MPP) and ERK inhibitor (PD98059). FMN alleviated depressive-like behaviors and preserved hippocampal integrity in mice. Bioinformatics analysis revealed FMN's strong binding to ER subtypes and enrichment in estrogen/MAPK pathways. In vitro, FMN pretreatment activated the ERK-CREB-BDNF axis in CORT-injured HT22 cells, enhancing neuronal survival and synaptic function. The activation was ERα/ERK-dependent, as evidenced by the abolition of protective effects following pharmacological inhibition with MPP (ERα antagonist) or PD98059 (ERK inhibitor). Concomitantly, in vivo FMN treatment restored hippocampal p-ERK/ERK ratios in mice, directly corroborating the ERK-CREB-BDNF pathway activation and highlighting its efficacy in reversing CORT-induced signaling deficits. FMN exerts antidepressant effects via ERα-mediated neurotrophic signaling (ERK-CREB-BDNF), offering a mechanistic foundation for natural antidepressant development. Show less

To identify associations of polymorphic variants of the genes of Two hundred thirty-five patients with AfD and 62 patients with AR and comorbid AlD aged 18 to 65 years were examined. The severity of AfD was assessed using the Structured Interview Guide for the Hamilton Depression Rating Scale, Seasonal Affective Disorder Version (SIGH-SAD) and the Clinical Global Impression (CGI), and the level of anxiety was assessed using the Hamilton Anxiety Rating Scale (HARS) at baseline and on Day 28 of psychopharmacotherapy. Polymorphic variants rs6265, rs7124442, rs11030104, and rs7103411 of the In AfD patients, rs3924999* The polymorphic variants rs3924999 of the Show less

Treatment-resistant depression (TRD) remains a complex challenge, often requiring interventions beyond standard medications. This review explores factors that may predict positive response to electroconvulsive therapy (ECT), repetitive transcranial magnetic stimulation (rTMS) and ketamine-based treatments to help guide clinical decision-making. A systematic review was conducted following PRISMA 2020 guidelines. English-language, peer-reviewed studies were identified through PubMed, Embase and Google Scholar using search terms such as 'treatment-resistant,' 'outcome,' 'prediction,' 'ECT,' 'rTMS,' and 'ketamine.' Studies were included if they examined clinical, biological or imaging predictors of response in adults with TRD. Case reports, reviews, editorials and non-English articles were excluded. A total of 42 studies were selected from 408 screened. Among these, 23 focused on ketamine/esketamine, 14 on rTMS, and 11 on ECT. Predictive factors were grouped into clinical (e.g., symptom profile, illness duration), biological (e.g., IL-6, CRP, BDNF) and imaging (e.g., cingulate cortex activity, connectivity). Inflammation markers and fronto-limbic network findings appeared across treatments, though findings were inconsistent. While some predictors show promise, clinical use remains limited by methodological differences and small sample sizes. Larger studies are required to identify clinically useful predictors. Additionally, for optimal treatment decision-making, comparative studies are necessary. Show less

Aurantii Fructus (AF)is a traditional Chinese medicine historically used to regulate Qi and alleviate emotional distress, suggesting potential psychotropic effects. This study investigates its therapeutic value for depression based on this traditional indication. To evaluate the rapid antidepressant-like effect of a single acute dose of AF extract in a chronic unpredictable mild stress (CUMS) mouse model and elucidate its underlying molecular mechanisms through integrated transcriptomic and metabolomic analyses. AF flavonoid content was quantified by HPLC. Male mice underwent a 4-week CUMS protocol. A single oral dose of AF was administered 2 h prior to behavioral testing (NSF, TST, SPT, and OFT), with ketamine serving as a positive control. Hippocampal transcriptome analysis was performed by RNA sequencing, and serum metabolites were profiled via LC-MS in both positive and negative ion modes. Pearson correlation analysis assessed relationships between key targets and behavioral outcomes. Pathway involvement was functionally validated in a separate experiment using a hypoxanthine synthesis inhibitor. AF contained narirutin (1.32 mg/g), hesperidin (3.19 mg/g), neohesperidin (22.89 mg/g), naringenin (0.03 mg/g), and nobiletin (0.08 mg/g). Acute AF administration rapidly reversed CUMS-induced depressive-like behaviors, significantly decreasing latency to feed and increasing food consumption in the NSF test, reducing immobility time in the TST, and elevating sucrose preference in the SPT, without altering locomotor activity. Transcriptomic analysis revealed specific downregulation of hippocampal caspase-4 expression by AF. Metabolomic profiling showed AF normalized elevated serum hypoxanthine levels. Serum hypoxanthine levels negatively correlated with hippocampal caspase-4 expression and behavioral improvements, whereas caspase-4 expression positively correlated with behavioral deficits. Pharmacological inhibition of hypoxanthine synthesis abolished AF's antidepressant effects and prevented its normalization of hippocampal caspase-4, NF-κB, GDNF, and BDNF expression. Acute AF produces rapid, ketamine-like antidepressant effects by targeting the hypoxanthine-caspase-4 pathway. This study reveals a novel purinergic mechanism underlying AF's traditional use for emotional disorders and offers a promising therapeutic strategy for rapid-acting antidepressant development. Show less

Depression imposes significant social, economic, and health burdens worldwide. Although phlorotannin-rich extract from Ecklonia cava (PS) and its active compound dieckol (DK) exhibit various biological activities, their antidepressant- and anxiolytic-like effects and underlying mechanisms remain unclear. This study investigated the antidepressant- and anxiolytic-like potential of PS and DK in a corticosterone (CORT)-induced mouse model of depression and anxiety, focusing on glucocorticoid receptor (GR) signaling. CORT-treated mice were orally administered PS or DK, and behavioral tests were performed to assess depressive- and anxiety-like behaviors. PS composition was analyzed using LC-MS/MS. Molecular docking predicted the binding of PS components to GR. GR nuclear translocation, target gene expression, and downstream signaling were examined using behavioral, molecular, and computational approaches. PS alleviated CORT-induced depressive- and anxiety-like behaviors, accompanied by reduced GR nuclear translocation, suppression of Mkp-1, and restoration of ERK-CREB-BDNF signaling. Molecular docking analysis predicted strong binding of DK to the GR ligand-binding domain. Consistently, DK reduced GR nuclear translocation and GRE binding, downregulated GR target genes (Mkp-1, Sgk-1, Fkbp5, and Bdnf), and restored ERK-CREB-BDNF signaling. In vivo, DK also improved CORT-induced behavioral deficits and normalized HPA axis activity and neurotransmitter levels. Collectively, our results suggest that DK, a major bioactive phlorotannin from E. cava, exerts antidepressant- and anxiolytic-like effects in association with modulation antagonism of GR signaling, highlighting its therapeutic potential as a natural GR-modulating agent for stress-related mood disorders. Show less

Depression, a complex global disorder with unmet therapeutic needs, imposes profound societal burdens. Yueju Pill (YJP), a classic TCM formula targeting 'six stagnations', synergistically integrates five herbs (Atractylodes, Cyperus, Ligusticum, Gardenia and Massa Medicata) to restore Qi-blood homeostasis. Contemporary evidence delineates its multitarget antidepressant efficacy: normalising monoaminergic neurotransmission and the tryptophan-kynurenine pathway, potentiating neurotrophic support (BDNF/eEF2) for neuroplasticity, antagonising neuroinflammation via microglial M1-to-M2 polarisation and NF-κB/MAPK inhibition, mitigating oxidative stress and mitochondrial dysfunction and enhancing synaptic plasticity through glial/neuronal gene regulation (e.g., GADD45g/PHGDH). This synthesis of TCM principles with mechanistic evidence positions YJP as a holistic, systems-level therapeutic candidate, advocating for rigorous clinical validation and integration into precision psychiatry. Show less

Depression is a prevalent mental disorder in modern society, with a complex and incompletely understood etiology. Accumulating evidence indicates that pesticide exposure is a potential risk factor for mental health disorders. Atrazine (ATR), a widely used herbicide with the highest global application rates and frequently detected in environmental media, has been confirmed to possess neurotoxicity. However, there are currently no reports examining its effects on depression. Therefore, this study aimed to investigate the effects of subchronic ATR exposure on depression-like phenotypes in mice through behavioral tests, pathological examinations, and molecular analyses. The results demonstrated that ATR exposure induced significant depressive-like behaviors and led to neuronal reductions in key brain regions associated with depression, such as the hippocampus and prefrontal cortex. These effects were mechanistically linked to oxidative damage and decreased expression levels of 5-hydroxytryptamine (5-HT) and brain-derived neurotrophic factor (BDNF). Collectively, this study not only reveals the potential role and mechanism of ATR as an environmental risk factor for depression, but also provides a theoretical basis for the prevention and treatment of its new neurotoxicological effects and future related research. Show less

With a global annual cumulative incidence of depression at 4.5% in community-dwelling older adults, understanding non-pharmacological interventions is essential. This narrative review explores the neuroprotective mechanisms of physical activity (PA) on brain function and mental health in individuals aged 60 and older. We conducted a search across multiple databases (MEDLINE, PsycINFO, EMBASE) using keywords related to aging, cognition, and physical activity. Our analysis of relevant studies shows that PA benefits the brain through several pathways. Early findings focused on improved cerebral blood flow and glucose utilization. More recent evidence highlights that PA increases neurotrophic factors like BDNF and IGF-1, enhances mood-regulating neurotransmitters, and promotes structural adaptations in key brain regions. These findings suggest that PA is a cost-effective, multi-domain intervention. This review provides healthcare professionals with actionable evidence to incorporate PA into clinical practice for older adults. Show less

Patients with inflammatory bowel disease (IBD) commonly exhibit psychiatric symptoms, such as anxiety and depression. However, studies on drugs addressing the concurrent amelioration of these symptoms in this patient population are rare. Previous studies have suggested that dihydromyricetin (DHM) may show therapeutic potential for IBD. This study investigated the therapeutic effects of DHM on dextran sulfate sodium (DSS)-induced colitis and associated behavioral disorders in mice. The findings of the experiments indicated that DHM could ameliorate colitis symptoms, including changes in body weight, colon length, disease activity index (DAI) scores, and histopathological damage. Furthermore, DHM improved the behavioral impairments observed in colitis mouse model, as evidenced by results from the open field test, elevated plus maze test, and tail suspension test, along with hippocampal histopathological assessments. Molecular analysis revealed that DHM notably suppressed the activation of NLRP3 inflammasome and IL-1β in both the colon and the hippocampus. DHM enhanced the intestinal barrier, elevated brain-derived neurotrophic factor (BDNF) levels in the hippocampus and serum, and concurrently reduced microglia activation. DHM lowered the levels of IL-1β, tumor necrosis factor-α (TNF-α), and lipopolysaccharide (LPS) in the serum. 16S rDNA sequencing results indicated that DHM could modulate DSS-induced gut microbiota dysbiosis, enriching various beneficial metabolic and neuromodulatory pathways. Metabolomic analysis demonstrated that DHM notably elevated acetic acid, propionic acid, and butyric acid levels in intestinal feces. Network pharmacology analysis identified the central intersecting genes of DHM, ulcerative colitis (UC), and neuroinflammation. Differential gene expression analysis underscored IL-1 β as a pivotal target for the co-occurrence of UC and psychiatric conditions. These findings imply that DHM may ameliorate DSS-induced colitis and concomitant behavioral disturbances in mice, underscoring its potential as a natural therapeutic agent for IBD accompanied by psychiatric comorbidities. Show less

The lifetime prevalence of depression is significantly higher in women. But the lack of ideal antidepressant severely limits therapies for female specific depressive disorders like perinatal depression. Herein, we evaluated whether vitamin C (ascorbic acid), a widely used nutritional supplement and perinatal therapeutic agent, could serve as a potential treatment for female-related depressive disorders using a chronic restraint stress (CRS) mouse model. C57BL/6 adult female mice were submitted to a 14-day CRS paradigm to induce depression-like behaviors. The antidepressant potential of vitamin C (200 mg/kg, i.p., a single dose) were assessed in CRS-exposed female mice that exhibited depression-like phenotype. Furthermore, we explored the underlying mechanisms through RNA sequencing, western blotting, and pharmacological interventions. Vitamin C rapidly ameliorated depression-like phenotypes in CRS-exposed female mice within 24 h. The sucrose preference test indicated that the antidepressant effect of vitamin C lasted for more than 72 h. Transcriptome sequencing analysis revealed that vitamin C reversed CRS-induced transcriptional alterations in 104 genes in the medial prefrontal cortex (mPFC) of female mice, including the dopamine receptor D2 (D2R). Western blotting confirmed that CRS suppressed the D2R-ERK1/2-CREB-BDNF pathway in the mPFC, which was effectively rescued by vitamin C. The antidepressant effect of vitamin C was antagonized by the D2R antagonist sulpiride. Additionally, protein-protein interaction network analysis revealed functional linkages between D2R and other vitamin C-regulated stress-sensitive genes. Our findings suggest that vitamin C may serve as an ideal candidate for the treatment of depression in females, potentially through the restoration of the D2R-BDNF pathway. Show less

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs), originally developed for type 2 diabetes mellitus (T2DM) and obesity, show promising potential as a novel treatment for depression, particularly in patients with comorbid metabolic disorders. This narrative review examines the bidirectional relationship between obesity and depression, driven by shared mechanisms such as chronic low-grade inflammation, hypothalamic-pituitary-adrenal axis dysregulation, and impaired neuroplasticity. GLP-1 RAs, including liraglutide and exenatide, demonstrate neuroprotective effects by enhancing brain-derived neurotrophic factor expression and synaptic plasticity, alongside anti-inflammatory properties that reduce proinflammatory cytokines (e.g., tumor necrosis factor-alpha and interleukin-6). They also modulate serotonin turnover in mood-regulating brain regions, mirroring selective serotonin reuptake inhibitors. Preclinical studies in animal models reveal improved behavioral outcomes, while human observational studies and limited clinical trials, such as the LEAD-3 trial, report enhanced mood and quality of life in T2DM and obesity patients. However, challenges, including high treatment costs ($800-$1000/month), injectable administration, and needle-related anxiety, limit patient adherence, and clinical adoption. The lack of large-scale randomized controlled trials targeting depression as a primary outcome further hinders definitive conclusions. This review highlights GLP-1 RAs' potential to address both metabolic and depressive symptoms, offering a holistic approach to managing these interconnected conditions. Future research should focus on long-term efficacy, optimal dosing, and overcoming adherence barriers to establish GLP-1 RAs as a viable psychiatric treatment. Show less

Depression is a multifactorial, chronic disorder and represents a leading cause of disability, with women exhibiting nearly twice the lifetime prevalence compared to men. Growing evidence indicates that this disparity cannot be explained by hormonal or psychosocial factors, but rather by dynamic interactions between environmental exposures, neuroendocrine signaling, and epigenetic regulation across development. This mini-narrative review aimed to examine how sex-specific exposome components interact with epigenetic mechanisms and synaptic remodeling processes to influence vulnerability to Major Depressive Disorder in women. The reviewed evidence demonstrates that fluctuations in ovarian hormones modulate HPA axis responsivity, neuroinflammatory signaling, and glutamatergic transmission through epigenetic regulation of stress-responsive genes such as Show less

For decades, major depressive disorder was attributed to a deficit in monoamine neurotransmitters. Clinical latency of tricyclic and selective serotonin reuptake inhibitors, high nonresponse rates, and inconsistent genetic findings challenged this view and redirected research toward downstream biology. Preclinical work revealed that chronic stress triggers dendritic and spine loss in the hippocampus and prefrontal cortex, whereas all effective treatments-including slow-acting monoaminergic drugs, rapid-acting ketamine, electroconvulsive therapy, and aerobic exercise-restore synapse number and function through brain-derived neurotrophic factor, TrkB, and mTOR signaling. Human connectomic studies then reframed depression as a disorder of mistimed large-scale networks; targeted neuromodulation of nodes intrinsically anticorrelated with the subgenual cingulate provides proof of concept. Parallel findings in immunology and gut-brain science show that psychosocial stress, peripheral cytokines, and metabolic cues converge on the same plasticity pathways, dissolving the historical boundary between "reactive" and "endogenous" depression. Ketamine crystallizes this multiscale model: within minutes, it induces dendritic-spine formation, normalizes default-mode and limbic connectivity, and relieves symptoms within hours. We synthesize these lines of evidence into a framework of precision synaptic psychiatry, in which pharmacological, neuromodulatory, and lifestyle interventions are selected according to biomarkers that index glutamatergic tone, inflammatory load, or network dynamics. Future therapeutics will be judged less by the neurotransmitters they influence and more by their capacity to restore flexible, resilient brain circuitry. Show less

Although chemotherapy remains a life-saving intervention for numerous cancer patients, it is often accompanied by depressive symptoms and cognitive impairments, "chemobrain." Noteworthy, multiple studies emphasize the role of glycogen synthase kinase 3β (GSK-3β) in depression and chemobrain; nevertheless, no available data relate GSK-3β inhibitors to chemobrain. Herein, this study aims to investigate the effect of the GSK-3β inhibitor, lithium, on behavioral and neurobiological abnormalities in a doxorubicin (DOX)-induced rat model of chemobrain. The chemobrain model was established through weekly intraperitoneal injections of doxorubicin (2 mg/kg/wk) for a duration of 4 weeks, whereas lithium (100 mg/kg/d, i.p.) was administered concomitantly over the same period. Behavioral, neurochemical, and histopathological evaluations were performed after the experimental protocol. DOX-induced depressive-like behaviors and cognitive impairments, with reduction in prefrontal cortex tropomyosin receptor kinase B receptors, brain-derived neurotrophic factor protein kinase B (BDNF), and phosphorylated protein kinase B, elevating the levels of the active form of GSK-3β, which lessened phosphorylated mammalian target of rapamycin/nuclear factor-erythroid 2-related factor 2/heme oxygenase-1 and BDNF/synapsin-1 pathways, while triggering overexpression of NF-κB, proinflammatory cytokines, oxidative stress, apoptosis, tau hyperphosphorylation, and neurodegeneration. Lithium ameliorated DOX-induced behavioral, neurochemical, and histological abnormalities. To the best of our knowledge, this study presents the first evidence that lithium treatment can modulate DOX-induced depression and cognitive deficits, potentially through revamping the BDNF/tropomyosin-related kinase receptor B/protein kinase B/GSK-3β/mammalian target of rapamycin/nuclear factor-erythroid 2-related factor 2/heme oxygenase-1 signaling cascade, thereby attenuating oxidative stress, neuroinflammation, apoptosis, neurofibrillary tangles, and subsequent neurodegeneration. SIGNIFICANCE STATEMENT: To the best of our knowledge, this study is the first to detect antidepressant and procognitive effects of lithium in DOX-induced chemobrain via GSK-3β inhibition. Accordingly, lithium offers a promising therapeutic target for the management of chemotherapy-induced depression and chemobrain. Show less

Current monoaminergic antidepressants demonstrate limited efficacy and delayed onset, necessitating novel treatment strategies. Previous studies have identified salt-inducible kinase 1 (SIK1) in the paraventricular nucleus (PVN) as an important regulator of depression pathogenesis by controlling nuclear translocation of cAMP response element-binding protein (CREB)-regulated transcription coactivator 1 (CRTC1) and activity of the hypothalamus-pituitary-adrenal (HPA) axis. The current study investigated the antidepressant-like efficacy of phanginin A, a newly discovered potent SIK1 activator, in male C57BL/6 J mice. Two well-validated depression models (chronic social defeat stress and chronic unpredictable mild stress) were established to examine the efficacy of phanginin A treatment against chronic stress-induced HPA hyperactivity and depression-like behaviors including desperate mood, anhedonia, and social avoidance. Western blotting, immunofluorescence, and co-immunoprecipitation were then conducted to evaluate the biological changes in not only the SIK1-CRTC1 signaling in PVN neurons but also the hippocampal brain derived neurotrophic factor (BDNF) signaling and adult neurogenesis among all groups. To further determine the antidepressant mechanism of phanginin A, model mice were re-examined following genetic knockdown of SIK1 in the PVN. Phanginin A administration suppressed depression-like behaviors in both models, normalized chronic stress-induced alteration in the SIK1-CRTC1 signaling in PVN neurons, and rescued chronic stress-induced impairments in hippocampal BDNF signaling and adult neurogenesis. Knockdown of SIK1 in the PVN abrogated the antidepressant-like actions of Phanginin A in male mice. Our findings further establish SIK1 in the PVN as an antidepressant target and support phanginin A as a potential antidepressant candidate. Show less

Depression is a major global health burden, and current treatments are limited by delayed onset and incomplete efficacy, highlighting the need for novel, mechanism-based therapies. Chronic restraint stress (CRS) induces behavioral, hormonal, and synaptic changes relevant to depression, but the role of adiponectin signaling remains unclear. Here, we examined whether the adiponectin receptor agonist AdipoRon exerts antidepressant-like effects via brain-derived neurotrophic factor (BDNF)/tropomyosin receptor kinase B (TrkB) signaling in mice subjected to 14 days of CRS. CRS produced anxiety- and depression-like behaviors, elevated plasma corticosterone, reduced circulating adiponectin, and selectively decreased hippocampal adiponectin and adiponectin receptor 2 (AdipoR2), accompanied by reduced PSD-95 and GluA1 in CA3 and the dentate gyrus (DG). AdipoRon treatment (20 mg/kg, days 8-14) prevented behavioral deficits, normalized corticosterone and adiponectin levels, and restored hippocampal AdipoR2, PSD-95, and GluA1 expression in CA3 and DG. AdipoRon also reversed CRS-induced decreases in hippocampal phosphorylated AMPK (p-AMPK), PPARα, BDNF, and phosphorylated TrkB (p-TrkB), with p-AMPK/AMPK and PPARα levels positively correlating with BDNF. Immunofluorescence confirmed BDNF recovery in CA3 and DG. Importantly, pretreatment with the TrkB antagonist ANA-12 abolished the behavioral, hormonal, and molecular effects of AdipoRon, indicating that its actions require BDNF-TrkB activation. These findings suggest that AdipoRon mitigates CRS-induced deficits via hippocampal AdipoR2-AMPK-PPARα-BDNF-TrkB signaling and highlight AdipoR2 as a promising target for depression therapy under chronic stress. Show less

Growing evidence suggests that resveratrol possesses neuroprotective properties against arsenic toxicity. This study investigated whether resveratrol could ameliorate arsenic-induced depression-like behaviors in male Naval Medical Research Institute (NMRI) mice and explored potential molecular mechanisms. Mice were exposed to arsenic (50 mg/L in drinking water) for 4 weeks and treated with resveratrol (10 or 20 mg/kg). Behavioral assessments included the hole-board test (HBT) for exploratory behavior, and the sucrose splash test (SST), tail suspension test (TST), and forced swim test (FST) for depression-like behaviors. The mRNA levels of Bdnf, Creb1, and Dvl1 in the brain were analyzed by qRT-PCR. Arsenic exposure induced significant depression-like behaviors, characterized by decreased grooming in SST and increased immobility in TST and FST. Resveratrol treatment prevented these behavioral alterations and exhibited intrinsic antidepressant effects in naïve mice, with dose-dependent reductions in immobility time (FST) and increased grooming (SST). Notably, resveratrol (20 mg/kg) enhanced rearing frequency in naïve mice and decreased it in the arsenic-treated mice. At the molecular level, arsenic downregulated Bdnf expression, while resveratrol restored its levels. In contrast, no significant changes in Creb1 and Dvl1 expression were observed. These findings indicate that resveratrol mitigates arsenic-induced depression-like behaviors primarily through the modulation of Bdnf-dependent pathways, independent of Creb1 and Dvl1. These results position resveratrol as a potential antidepressant and underscore its therapeutic promise for mood disorders associated with environmental toxicant exposure. Show less

Psilocybin-containing mushrooms, commonly known as magic mushrooms, strongly affect mood, cognition, and behavior. Psilocybe azurescens is a species of psilocybin mushrooms that contains the main active compounds psilocybin and psilocin. Psilocybin mushrooms have been used since ancient times to improve the quality of life. However, their adverse effects have been less studied. This study aimed to investigate, for the first time, the effect of oral consumption of P. azurescens on social behavior, anxiety- and depressive-like behaviors in rats. The underlying mechanisms of these behaviors were also studied. Male Wistar rats received three doses of P. azurescens (10, 100, and 250 mg/kg) by gavage every other day for 14 days. Social interaction, anxiety- and depressive-like behaviors were assessed using the three-chamber, elevated plus maze, and forced swimming tests, respectively. Protein levels of neurotrophic (BDNF and GDNF), neuroinflammatory (IL-6 and TNFα), and oxidative stress (ROS and SOD) factors were measured in the hippocampus, prefrontal cortex (PFC), and amygdala by ELISA technique. The results showed that P. azurescens significantly increased anxiety- and depressive-like behaviors and disrupted social interaction behavior in rats. These effects were accompanied by increased neuroinflammation and oxidative stress and decreased neurotrophic factors in the hippocampus, PFC, and amygdala. This study suggests that the high doses of P. azurescens can cause mood disorders by increasing inflammatory responses and oxidative stress and decreasing the expression of neurotrophic factors. Show less

Growing evidence implicates accelerated biological aging in environmentally induced psychiatric disorders, yet its role in metal-associated depression remains unclear. Using NHANES data, we evaluated associations between heavy metal mixtures and depression. Bidirectional mediation analysis was used to assess reciprocal pathways linking heavy metals, biological aging, and depression. Simultaneously, candidate genes linking heavy metal exposure to depression and biological aging were identified by mining the Comparative Toxicogenomics Database, analyzing differentially expressed genes (DEGs) from the Gene Expression Omnibus, and integrating the resulting evidence within a toxicogenomic framework to explore potential molecular mechanisms. The prevalence of depression among participants was 8.66 %. Metal mixtures significantly increased depression risk. Notably, cadmium and antimony increased the risk of depression (OR: 1.52, 95 % CI: 1.19, 1.94 and OR: 1.54, 95 % CI: 1.22, 1.93). Both metals have low thresholds (0.227 μg/L and 0.053 μg/L, respectively). Additionally, lead, cobalt, and molybdenum showed positive associations in specific models. Although population-level exposure to heavy metals declined from 1999 to 2020, concentrations remained sufficient to elevate depression risk. Our correlation analysis also identified a strong correlation between PhenoAge and chronological age (r = 0.84, P < 0.001). Mechanistically, we found that accelerated PhenoAge partially mediated the associations of several metals with depression risk, including monomethylarsonic acid (β = 0.004; 95 %CI: 0.003,0.006), cadmium (β = 0.006; 95 %CI: 0.003, 0.010), lead (β = 0.009; 95 %CI: 0.006, 0.011), cobalt (β = 0.010; 95 %CI: 0.006, 0.013), molybdenum (β = 0.009; 95 %CI: 0.006, 0.011), and antimony (β = 0.008; 95 %CI: 0.005, 0.011). Pathway analysis and DEGs implicated the contribution of neurodegeneration-multiple diseases pathway, with core molecular targets centering on BDNF, IL6, GSK3B, PTGS2, and SOD1. These findings, which imply biological aging as a potential link between metal exposure and depression, call for revised safety thresholds and pinpoint molecular targets for intervention. Show less

Despite available therapies for depression, many patients do not achieve adequate improvement, illustrating the need for innovative treatment strategies. Nutritional psychiatry is an emerging area, with increasing evidence that microbially derived butyrate contributes to the beneficial effects of dietary, pre-, pro- and synbiotics interventions - raising the exciting possibility that direct butyrate administration might alleviate depressive symptoms. The main objective was to systematically review the effects of butyrate on depressive symptoms in humans and depressive-like behavior in animals (PROSPERO; CRD42023g0739). A search was conducted in MEDLINE, Embase, PsycINFO, and Web of Science, ICTPR and ClinicalTrials.gov up to October 2025. Studies were included if they examined depressive symptoms in humans or relevant behaviors in animal models of depression/anxiety, involved treatment with butyrate formulations, included a control or pre-post comparison, and reported behavioral or clinical outcomes. Eligible designs included case-control, cohort, (randomized) controlled trials, experimental, or in vivo studies published in English or Dutch. Studies were excluded if depression was not the primary focus or if butyrate was combined with another treatment. Risk of bias was assessed with SYRCLE for animal studies and RoB 2 for the human studies. Of the two randomized controlled trials, one found no measurable effect of 1-week oral butyrate in healthy males, whereas the other found reductions in depressive and anxiety symptoms in patients with ulcerative colitis after 12-weeks oral butyrate. Thirty-two animal studies showed that butyrate generally modulated depressive- and anxiety-like phenotypes in rodents, potentially via anti-inflammatory, neuroplastic, epigenetic and gut-mediated mechanisms. Preclinical findings support the therapeutic promise of butyrate as a novel intervention for depression, warranting further clinical investigation. BDNF, Brain-derived neurotrophic factor; CRS, Chronic restraint stress; CSD, Chronic social defeat; CUMS, Chronic unpredictable mild stress; DASS, Depression, anxiety, Stress Scales; EPM, Elevated plus maze; FMT, Fecal microbiota transplant; FST, Forced swim test; HDAC, Histone deacetylase; HFD, High-fat diet; HPA, Hypothalamic-pituitary-adrenal; ICTRP International Clinical Trials Registry Platform; IL, Interleukin; LDB, Light-dark box; LEIDS-R, Leiden Index of Depression Severity-Revised; LPS, Lipopolysaccharide; MD, Maternal deprivation; MDD, Major depressive disorder; MGBA, Microbiota-gut-brain axis; NORT, Novel object recognition test; OFT, Open field test; PFC, Prefrontal cortex; PRISMA Preferred reporting items for systematic reviews and meta-analyses; SCFA, Short-chain fatty acid; SPT, Sucrose preference test; SYRCLE, Systematic Review Centre for Laboratory Animal Experimentation; TCA, Tricarboxylic acid; TNF, Tumor necrosis factor; TST, Tail suspension test; ZO-1, Zonulin-1. Show less

Electroconvulsive therapy (ECT) stands as the most effective intervention for treatment-resistant depression; however, its interaction with dietary regulation of the gut-brain axis has not been thoroughly explored. This study aimed to elucidate the mechanistic link between ECT, gut microbiota remodeling, short-chain fatty acid (SCFA) production, and neural plasticity. In this study, mice were subjected to chronic restraint stress (6 h/d for 28 consecutive days) to establish a depression-like model. Utilizing a translational approach that incorporated behavioral assessments, multimodal neuroimaging techniques such as PET-CT and laser speckle contrast imaging, along with multiomics analyses including metagenomics, metabolomics, and transcriptomics in rodent models, we demonstrated that ECT induced significant gut microbiota remodeling, characterized by an enrichment of SCFA-producing genera like Lactobacillus and Bifidobacterium. This remodeling was associated with restored intestinal barrier integrity and elevated plasma SCFA levels. Mechanistically, these microbial metabolites activated hippocampal Wnt/β-catenin signaling pathways, enhancing synaptic plasticity restoration, while concurrent probiotic supplementation further amplified brain-derived neurotrophic factor (BDNF) expression via SCFA-dependent epigenetic mechanisms. Neuroimaging corroborated the normalization of cerebral glucose metabolism and hemodynamic function post-ECT. In conclusion, our findings unveil a novel gut-brain communication pathway by which ECT exerts its antidepressant effects, positioning SCFAs as vital mediators connecting microbial metabolic alterations to neural plasticity. This research not only redefines the role of nutritional biochemistry in neuromodulation but also suggests the potential of microbial metabolite monitoring to tailor antidepressant therapies for enhanced efficacy. Show less

Depression is a debilitating psychiatric disorder with high prevalence and suicide risk, imposing significant burdens on global health. Against this global health burden, the active ingredients of Gekko gecko Linnaeus (AIGG), a traditional Chinese medicine (TCM), have shown empirical antidepressant effects. However, their specific pharmacological mechanisms remain unclear. This study systematically elucidated the antidepressant mechanisms of AIGG by integrating GC-MS-based component analysis, network pharmacology, molecular docking, and a corticosterone (CORT)-induced depressive mouse model. GC-MS identified 10 bioactive compounds (including fatty acids) in AIGG. Network pharmacology screening of 51 potential targets revealed significant enrichment in synaptic transmission and cAMP pathways. Molecular docking confirmed strong binding affinities between AIGG-derived compounds and key targets. In vivo experiments demonstrated that AIGG significantly reversed depression-like behaviors in both forced swim and tail suspension tests, suppressed Interleukin-6 (IL-6), tumor necrosis factor α (TNF-α), and elevated β-nerve growth factor (β-NGF) levels, attenuated neuroinflammatory infiltration and neuronal apoptosis in brain tissue, and upregulated protein expression of protein kinase cAMP-activated catalytic subunit alpha (PRKACA), brain-derived neurotrophic factor (BDNF), and postsynaptic density protein 95 (PSD95). The study confirmed that AIGG alleviates depression by activating the cAMP-PRKACA-BDNF axis to restore synaptic plasticity, providing a novel natural product-based strategy for treatment of the resistant depression. Show less