Search Results (2,950)

The use of animal models to study mental illnesses, such as depression, requires proper standardization and extensive expertise. Achieving good construct, face, and predictive validity in depression models is quite challenging. Currently, only a few environmental models, mostly based on chronic stress, and a limited number of genetic models fulfill these criteria. In the quest for new antidepressants, initial screening tests are employed as a preliminary step in research. While these tests do not always meet the requirements of a disease model, they are useful for the early identification of substances that may have antidepressant potential, paving the way for further studies based on established models. This approach to discovering antidepressants was originally designed for traditional medications, which typically act by modulating serotonergic, noradrenergic, and dopaminergic systems, and require multi-week administration to produce a therapeutic effect. In contrast, the new antidepressant ketamine offers rapid therapeutic effects following a single dose and exhibits distinctive behavioral outcomes in both screening tests and animal depression models. These effects have inspired a new model for the search for rapid-acting ketamine-like antidepressants. This review presents the behavioral effects of ketamine and discusses the methodologies used in the search for novel rapid-acting antidepressant drugs (RAADs). Full article

Background/Objectives: Real-world antidepressant use for depressive disorder varies across clinical settings. This study aimed to characterize prescribing pathways and evaluate the comparative safety of frequently prescribed antidepressants in a large multicenter cohort with newly diagnosed depressive disorder. Methods: We conducted a retrospective multicenter observational study using electronic health record data standardized to the OMOP Common Data Model (1999–2026) in adults initiating antidepressants. Prescribing patterns among 13,381 patients were visualized using sunburst plots and Sankey diagrams. Comparative safety, escitalopram vs. sertraline and trazodone, was evaluated across 18 hospitals (n = 44,542) for nine clinical safety outcomes using propensity score-matched Cox proportional hazards models and empirically calibrated random-effects meta-analysis. Results: Selective serotonin reuptake inhibitors, particularly escitalopram (21.4%, n = 2868), were the preferred antidepressant. Common adjunctive medications included trazodone (14.6%, n = 794) and quetiapine (14.0%, n = 761), though utilization varied across hospitals. No clear differences were detected for most safety outcomes between cohorts. However, empirically calibrated QTc prolongation risk was significantly increased with sertraline relative to escitalopram (HR 1.75, 95% CI 1.10–2.78), a signal requiring further confirmation. Conclusions: This study demonstrates substantial institutional variation exists in real-world antidepressant treatment pathways and combination strategies. While comparative safety profiles were broadly comparable across evaluated outcomes, the isolated QTc prolongation signal for sertraline warrants targeted external confirmation. Furthermore, trazodone and escitalopram cohorts should not be regarded as clinically interchangeable first-line options, supporting individualized, evidence-based antidepressant selection in routine clinical practice. Full article

Background: Long COVID has emerged as a global health challenge characterized by persistent neuropsychiatric symptoms, including depression, fatigue, and cognitive impairment. Growing evidence indicates that sustained neuroinflammation, endothelial dysfunction, and fronto-limbic network disruption may underlie these symptoms, representing pathophysiological features distinct from major depressive disorder (MDD). Although repetitive transcranial magnetic stimulation (rTMS) is an established treatment for MDD, its therapeutic efficacy in Long COVID-associated depression remains uncertain. Methods: Long COVID was defined as laboratory-confirmed SARS-CoV-2 infection followed by persistent neuropsychiatric symptoms lasting ≥3 months, including cognitive impairment (“brain fog”), fatigue, and new-onset depressive symptoms. We conducted a retrospective registry-based cohort study using real-world clinical data from two TMS clinics in Tokyo (May 2022–April 2026). Forty-four medication-free patients with Long COVID-associated MDD were compared with eighty-eight propensity score–matched patients with primary MDD (1:2 nearest-neighbor matching based on age, sex, and baseline Montgomery–Åsberg Depression Rating Scale (MADRS)). All participants received left dorsolateral prefrontal cortex intermittent theta burst stimulation (iTBS). Treatment outcomes were evaluated using MADRS and 17-item Hamilton Depression Rating Scale (HAM-D₁₇) improvement rates, HAM-D₁₇ response, and remission. Statistically adjusted analyses (inverse probability of treatment weighting (IPTW) and doubly robust estimation) were used to reduce measured confounding; however, residual unmeasured confounding cannot be excluded due to the retrospective observational design. Results: Long COVID patients showed significantly attenuated antidepressant response. Improvement rates were markedly lower for MADRS (38.4% vs. 61.5%) and HAM-D₁₇ (36.7% vs. 58.4%). IPTW and doubly robust models demonstrated large adjusted percentage-point differences (MADRS: −23.0 percentage points; HAM-D₁₇: −21.8 percentage points; both p < 0.001). While HAM-D₁₇ response did not differ significantly, remission rates were substantially reduced (27.3% vs. 61.4%). Conclusions: These findings indicate an adjusted association suggesting reduced rTMS responsiveness in Long COVID-associated depression. Given the retrospective observational design and the possibility of residual unmeasured confounding, the results should be interpreted as associations rather than evidence of a causal effect. Full article

Epidemiological and clinical evidence indicates that obesity-associated metabolic dysfunction increases the risk of depression, which is often resistant to conventional antidepressant therapies. Elucidating targeted mechanisms underlying obesity-related depression is therefore essential for developing effective interventions. Accumulating evidence identifies neuroinflammation as a central link between obesity and depressive disorders. Obesity-driven inflammatory signaling disrupts multiple neurobiological processes implicated in depression, thereby contributing to the onset and progression of inflammatory depression. Polyphenols, a diverse class of plant-derived secondary metabolites, have demonstrated neuroprotective properties, attributed to their anti-inflammatory, antioxidant, and metabolic regulatory effects. By restoring neurobiological homeostasis, polyphenols may represent a promising therapeutic strategy for obesity-related inflammatory depression. This review summarizes the pathophysiological mechanisms through which obesity induces neuroinflammation and subsequently promotes depressive symptoms. It further evaluates current evidence regarding the efficacy and effective dosing of polyphenols in attenuating inflammatory signaling and alleviating obesity-related inflammatory depression, as well as the translational challenges faced in their clinical application. Given their anti-neuroinflammatory potential, polyphenols may serve as a valuable adjunctive approach for the management of obesity-related inflammatory depression. Full article

Background: Traditional antidepressants are associated with undesirable side effects, limited efficacy, and delayed therapeutic responses. Natural products have emerged as a potential alternative to these drugs. This research aimed to investigate the antidepressant-like activity and possible mechanism of Orthosiphon stamineus (OS) leaf ethanolic extract. Methods: Molecular docking and in vitro studies were performed to assess the inhibitory activity of ethanolic extracts of OS leaves against the monoamine oxidase (MAO-A) enzyme. Behavioral tests were used to evaluate the antidepressant-like activity of the 95% ethanol extract in reserpine-treated rats, followed by histopathological examination and measurement of hippocampal serotonin (5-HT), norepinephrine (NE), and brain-derived neurotrophic factor (BDNF). Results: The main active compounds, particularly rosmarinic acid and eupatorin, exhibited favorable binding affinities to the MAO-A active site. The 95% and 50% ethanol extracts of OS showed dose-dependent MAO-A inhibitory activity with ICs50 of 88.67 and 103.2 µg/mL, respectively. The 95% ethanol extract of OS leaves showed a significant reduction in immobility time, restored locomotor activity, and preserved hippocampal morphology. Notably, the higher dose of OS extract (150 mg/kg) significantly enhanced hippocampal expression of 5-HT and NE, with a moderate upregulation of BDNF. Conclusions: These findings suggest that the 95% ethanol extract of OS leaves exhibits promising antidepressant-like effects, which may be mediated through monoamine modulation and BDNF expression and partially through MAO-A enzyme inhibition. Full article

Tilia americana var. mexicana is a medicinal species whose reported pharmacological effects primarily target the central nervous system, including anxiolytic, antidepressant, and anticonvulsant activities, attributed in part to flavonoids such as tiliroside (8). In this study, 14 compounds were isolated and identified from the methanolic extract (Ta-MeOH) and evaluated by molecular docking against the monoamine oxidases MAO-A and MAO-B, enzymes implicated in Parkinson’s disease (PD) due to their involvement in dopamine metabolism. Chemical analysis identified six terpenes: α- and β-amyrine (1–2), β-sitosterol (3), stigmasterol (4), ursolic acid (5), and β-sitosterol glucoside (6); the novel diglycosylated monoterpene 4α-terpineol sambubioside (7), characterized through its hexaacetate derivative (7a); the flavonoids tiliroside (8) and rutin (9); sucrose (10); and four phenolic compounds: scopoletin (11), caffeic acid (12), coumaric acid (13), and chlorogenic acid (14). Molecular docking against monoamine oxidases A and B (MAO-A and MAO-B) was used as a computational strategy to prioritize isolated metabolites for biological evaluation. β-Sitosterol glucoside (6), 4α-terpineol sambubioside (7), tiliroside (8) and rutin (9) exhibited the most favorable docking scores toward MAO-B, with predicted binding energies of −10.8733, −11.1434, −12.16986 and −12.9474 kcal/mol, respectively. Considering the docking results together with phytochemical and experimental criteria, (6) and (8) (1 mg/kg) were prioritized for biological evaluation, together with Ta-MeOH extract (100 mg/kg) and selected fractions (25 mg/kg), in a reserpine-induced mouse model of parkinsonism using L-DOPA (150 mg/kg) as a positive control. In the open field test, spontaneous locomotor activity was assessed by total crossings and expressed as AUC. Ta-MeOH significantly increased locomotor activity compared with the reserpine-treated group (AUC: 1281.8 vs. 551.7, respectively; p < 0.05). Tiliroside (8) also increased locomotor activity (AUC: 858). In the Rota-Rod test, fine motor coordination was assessed by latency to fall and expressed as AUC. Ta-MeOH showed the greatest recovery, with AUC values of 431, 89, and 34 at 4, 10, and 20 rpm, respectively. In addition, treatments derived from T. americana attenuated behavioral alterations induced by reserpine in the Irwin test. Overall, this study demonstrates that integrating phytochemical isolation, molecular docking, and in vivo pharmacological evaluation provides a useful strategy for prioritizing bioactive metabolites from T. americana. These findings support further pharmacological investigation of this medicinal species and its isolated metabolites, while additional studies are required to establish their molecular targets and mechanisms of action. Full article

Tobacco use remains one of the leading preventable causes of morbidity and mortality worldwide, contributing to more than 7 million deaths annually and imposing a substantial economic burden on healthcare systems and global productivity. The addictive properties of tobacco are primarily mediated by nicotine, which exerts its effects through neuronal nicotinic acetylcholine receptors (nAChRs) within brain reward circuits. Among these receptor subtypes, α4β2-containing nAChRs play a central role in nicotine dependence by regulating dopaminergic signaling associated with reinforcement, craving, withdrawal, and relapse. Repeated nicotine exposure induces neuroadaptive changes in receptor expression and neural circuitry, contributing to the chronic and relapsing nature of addiction. Advances in addiction neuroscience and receptor pharmacology have enhanced the understanding of nicotine-mediated signaling and facilitated the development of evidence-based smoking cessation therapies. Current treatment approaches include nicotine replacement therapies, antidepressant-based interventions, and partial nAChR agonists such as varenicline and cytisine. Emerging strategies encompass subtype-selective ligands, allosteric modulators, immunotherapeutics, neuromodulation techniques, and digital health technologies aimed at improving cessation outcomes. This review summarizes the neuropharmacological mechanisms underlying nicotine addiction and critically examines current and emerging therapeutic strategies, highlighting their mechanisms of action, clinical efficacy, limitations, and future potential for tobacco cessation. Full article

Treatment-resistant mental health conditions are common in primary care and challenging for clinicians. Trial-and-error prescribing can prolong morbidity and increase adverse drug reactions (ADRs). Pharmacogenomic (PGx) testing enables individualised prescribing by identifying gene–drug interactions affecting psychotropic response. Thirty adults with treatment-resistant mental health conditions underwent PGx testing using a commercial panel (one lost to follow-up [n = 29]). Patients received PGx-guided treatment (n = 8) or standard care (n = 21). Phenotypes were assigned per CPIC and DPWG guidelines, with prescribing guided by clinical experience where guidelines were unavailable. Medication histories were reviewed for gene–drug concordance, ADRs, and treatment failures. Clinical improvement at eight weeks was defined as “marked” or “moderate” improvement and/or ADR resolution. Actionable genotypes were common, particularly CYP2D6 (27.5% poor/intermediate drug metabolising phenotype) and CYP2C19 (37.9%). Guideline-actionable gene–drug interactions occurred in 37% of patients, and eleven patients possessed actionable phenotype at multiple loci. Gene–drug interactions were identified in nine patients and guidance was fully implemented in six. Clinical benefit at 8 weeks was achieved in 6/8 patients with genotype-guided changes versus 8/21 receiving standard care. PGx-guided prescribing may support improved antidepressant response and tolerability while reducing trial-and-error prescribing for treatment-resistant patients in primary care. Full article

Background: Depression is a multifactorial psychiatric disorder involving monoaminergic, neurotrophic, inflammatory, oxidative, and stress-response pathways. Centella asiatica and its triterpenoids have demonstrated neuroprotective and stress-modulating properties, but depression-focused evidence remains fragmented. Objective: The aim of this scoping review was to map the available evidence on C. asiatica, its standardized extracts, and its bioactive triterpenoids in relation to depression-related outcomes and mechanisms. Methods: A protocol was registered before formal screening, full-text assessment, data charting, and evidence synthesis (INPLASY202670003). Scopus, PubMed/MEDLINE, the Cochrane Library, and ClinicalTrials.gov were searched from inception to 2 July 2026. Eligible studies included human, animal, cell-based, and ex vivo studies reporting depression, depressive-like behavior, antidepressant-like effects, or mechanisms explicitly linked to depression-related pathophysiology. Two reviewers independently screened the identified records and charted the data using a standardized form, with disagreements resolved through consensus or consultation with a third reviewer. The findings were synthesized descriptively and narratively. Results: A total of 14 studies published between 2008 and 2025 were included, comprising 13 preclinical studies and 1 open-label human study. No eligible cell-based or ex vivo studies were identified. The included studies primarily examined C. asiatica extracts and isolated triterpenoids, particularly asiaticoside and asiatic acid. Most studies reported favorable depression-related or antidepressant-like findings. The principal reported mechanisms involved BDNF/CREB-related signaling and neuroplasticity, monoaminergic regulation, attenuation of neuroinflammation and oxidative stress, and modulation of the hypothalamic–pituitary–adrenal axis. However, the evidence base is heterogeneous and predominantly derived from animal models. Conclusions: The available evidence supports the biological plausibility and preclinical antidepressant-like activity of C. asiatica and its triterpenoids; however, the evidence remains insufficient to establish clinical efficacy in humans. Future studies should prioritize standardized preparations, dose justification, pharmacokinetic and safety evaluation, validated depression-specific outcomes, and rigorously controlled clinical trials. Full article

Major depressive disorder (MDD) is a heterogeneous psychiatric disorder characterized by impaired mood, neuroplasticity, neuroinflammation, and dysregulated stress response systems. Chronic stress can induce epigenetic changes leading to depression. Evidence suggests that histone acetylation and deacetylation are epigenetic processes involved in changes in gene expression. Histone deacetylases (HDACs) modulate chromatin structure and transcription, and their dysregulation is associated with stress susceptibility, decreased brain-derived neurotrophic factor (BDNF) signaling, impaired synaptic plasticity, and inflammatory activation. HDAC isoforms HDAC3 and HDAC6 have emerged as epigenetic regulators in stress-induced depression. HDAC3 is a transcriptional regulator involved in neuroplasticity-related gene expression, inflammatory signaling, and glucocorticoid receptor-mediated stress responses. In contrast, HDAC6 is cytoplasmic and regulates non-histone substrates involved in microtubule dynamics, synaptic function, protein trafficking, and the regulation of the hypothalamic–pituitary–adrenal axis (HPA axis). Preclinical studies show that HDAC3 or HDAC6 inhibition can exert antidepressant-like effects by promoting neuroplasticity, reducing neuroinflammation, and restoring stress-related signaling. Dual targeting is an interesting therapeutic approach because both regulate complementary mechanisms. However, clinical translation is limited by poor blood–brain barrier penetration, systemic toxicity, insufficient isoform selectivity, and a lack of clinical evidence. This review summarizes the roles and mechanisms of HDAC3 and HDAC6, the rationale for dual targeting, translational limitations, and future therapeutic perspectives. Full article

Depression is a prevalent and complex neuropsychiatric disorder that substantially impairs quality of life worldwide. Current pharmacological and psychotherapeutic interventions are often limited by inadequate efficacy and restricted accessibility. Exercise has emerged as a potent non-pharmacological alternative, exhibiting antidepressant effects comparable to conventional treatments, with the microbiota–gut–brain (MGB) axis increasingly recognized as a key mediator. Despite growing interest, existing research articles largely describe associations without mapping the molecular pathways from exercise-altered microbes to neurobiological changes in depression. This review addresses these gaps by comprehensively dissecting the molecular cascades from microbial remodeling to synaptic and systemic adaptations, thereby providing a mechanistic roadmap absent in current syntheses. We first delineate how gut dysbiosis contributes to depression via endocrine, neural, and immune pathways. Subsequently, we highlight the ability of exercise to reverse these pathological states by restoring microbial diversity, reinforcing intestinal barrier function, and modulating the production of microbial metabolites. These exercise-driven changes collectively attenuate systemic and neuroinflammation, enhance brain-derived neurotrophic factor signaling, augment serotonin synthesis, and dampen hypothalamic–pituitary–adrenal axis hyperactivity. By reinstating intestinal homeostasis, exercise acts as a central regulator of the MGB axis and represents a promising therapeutic strategy. This integrative framework offers novel insights into depression pathogenesis and opens avenues for multifaceted intervention. Full article

Background: Studies indicate that depression and cognitive functions are important issues of mental health, a serious health issue worth evaluating with possible alternative non-medical treatment options in MS patients. Aim: The aim of this study was to investigate the effect of practice on fatigue, respiratory closure, depression and cognition in patients diagnosed with MS and whether the benefit of Hatha Yoga training is affected by personality structure. Methods: The study included 25 participants between the ages of 18 and 70 who were diagnosed with MS, with an EDSS of 6 and below and who did not show symptoms of depression and did not use antidepressants. Any previous cerebrovascular disease, hypertension (HTN), diabetes mellitus (DM), thyroid dysfunction, or vitamin B12 deficiency was determined as an exclusion criterion. In the study, patients received Hatha Yoga practice 2 days a week for 8 weeks. The MOCA (Montreal Cognitive Assessment) and Beck Depression Scale, personality analysis test, pulmonary function test, and Fatigue Impact Scale were applied to all patients fulfilling the inclusion criteria at the beginning and after the completion of Yoga practice. Results: According to the results obtained, a statistically significant decrease in Beck Depression Inventory scores (p = 0.020) and a significant increase in MOCA Cognitive Test scores (p < 0.001) were detected following the yoga intervention. Although an increase was observed in respiratory capacity (FVC), this change did not reach statistical significance (p = 0.082). These findings demonstrate that yoga practice significantly improves depression levels and cognitive functions. The relationship between the benefits derived from yoga training and personality traits was evaluated using the participants’ Temperament and Character Inventory (TCI) profiles. Following the yoga intervention, a statistically significant increase was observed in novelty seeking (p < 0.001) and persistence (p < 0.001). Conversely, participants exhibited a significant decrease in harm avoidance post-yoga (p < 0.001). However, no statistically significant changes were found in reward dependence (p = 0.766) or cooperation (p = 0.181) scores after the intervention. Full article

Indoles are chemical compounds that naturally occur in Prokaryotes and Eukaryotes. For example, indole alkaloids mainly occur in plant families such as Nyssaceae, Rubiaceae, Apocynaceae, and Loganiaceae. The popularity of indoles has led to further research into their function and synthetic modification. Meanwhile, the Wnt (Wingless and Int-1) signaling pathway is responsible for cell regulatory processes, while its dysfunction often constitutes the molecular basis for the pathogenesis of neoplastic processes. Databases such as PubMed, Scopus, Google Scholar, and Science Direct were used to perform a literature search with keywords including “indoles” and those related to their biological activity, as well as “Wnt pathway” and “thyroid cancer (TC)”. We used ClinicalTrials.gov to search current clinical trials for selected indoles, such as melatonin, indole-3-propionic acid, and indole-3-carbinol. While indoles possess many therapeutic properties, we focused here on the following: antitumor, antiviral, anti-inflammatory, antidepressant, antimigraine, antiemetic, and antihypertensive activities. We analyzed the Wnt pathway and its disruptions in thyroid cancer. In this manuscript, seventy-six (76) indoles, which have natural and synthetic origins, are presented. In addition to all activities mentioned, we discuss the therapeutic goals of indole applications in anticancer research. The Wnt signaling pathway can be changed in tumor cells, and such disruptions can occur in thyroid cancers. Full article

Background/Objectives: The use of antidepressants and anxiolytics has increased worldwide, raising concerns about treatment patterns, medication safety, and rational use. This study aimed to characterize the frequency, utilization patterns, and safety-related aspects of antidepressant and anxiolytic use among healthcare students and university staff at a Brazilian public university. Methods: A cross-sectional study was conducted between September 2024 and June 2025 using an online questionnaire administered to students and staff at the University of São Paulo, Brazil. Descriptive statistics and multivariable logistic regression were applied to characterize medication utilization patterns and evaluate factors associated with antidepressant and/or anxiolytic use. Results: Among the 300 participants, 167 (55.7%) reported antidepressant and/or anxiolytic use during the previous six months. Most users reported treatment for more than one year (59.9%), anxiety as the primary indication (68.3%), and prescription by a healthcare professional (93.4%). A total of 203 medications were reported, with selective serotonin reuptake inhibitors being the most common pharmacological class (42.4%). Among users, 99 (59.3%) reported at least one self-reported adverse effect, most commonly excessive drowsiness, reduced libido/sexual dysfunction, dry mouth, headache, and nausea. No statistically significant independent associations were identified between antidepressant and/or anxiolytic use and the evaluated sociodemographic characteristics. Conclusions: Antidepressant and anxiolytic use was frequently reported and was characterized by predominantly long-term, professionally prescribed treatment and frequent self-reported adverse effects. These findings may inform institutional strategies to improve access to mental healthcare while promoting the rational and safe use of psychotropic medications within university settings. Full article

Depression is a leading cause of disability worldwide, and currently available antidepressants are limited by delayed therapeutic onset, inadequate efficacy in some patients, and adverse effects. G protein-coupled receptors (GPCRs), the largest family of membrane receptors in the central nervous system, regulate neurotransmission, neuroplasticity, neuroinflammation, stress responses, and reward processing, and are therefore important targets for antidepressant drug development. Natural products are a rich source of structurally diverse bioactive compounds, many of which show antidepressant-like effects through the modulation of GPCR-mediated signaling pathways. In this narrative review, we summarize the roles of major GPCR families implicated in depression and provide an updated overview of natural products that modulate these receptors. We particularly emphasize receptor-specific mechanisms, downstream signaling networks, and the pharmacological actions of representative natural compounds. We also highlight emerging concepts in GPCR biology, including receptor heteromerization, signaling bias, and allosteric modulation, that may create new opportunities for antidepressant discovery. Finally, we discuss current challenges related to target validation, pharmacokinetics, and clinical translation. Collectively, these insights support further investigation of natural product-derived GPCR modulators as potential leads for next-generation antidepressant development. Full article