Search Results (307)

Chiral pharmaceuticals (CPs) have gained growing attention in environmental studies regarding the differential behavior of individual enantiomers in racemic mixtures. This study investigates the stereoselectivity and efficiency of montmorillonite (MMT), a natural and low-cost adsorbent, for the removal of a wide group chiral pharmaceuticals and metabolites (atenolol, propranolol, metoprolol, fluoxetine, venlafaxine, norfluoxetine, and O-desmethylvenlafaxine). The effects of adsorption conditions including initial CP concentration, contact time, adsorbent dose, solution pH, and humic acid content were evaluated. In most adsorption experiments, no significant stereoselective behavior was observed, except for the case where a low adsorbent dose was applied. Interestingly, as the solution humic acid content increased (up to 40 mg/L), the adsorption capacity was increased for most of the target CPs. Isotherm studies revealed that the Freundlich model described the experimental data well and the process was favorable. Adsorption mechanism was interpreted by material characterization before and after adsorption. High removal efficiencies (88.0 to 99.8%) and the non-enantioselective behavior of MMT indicate that it can be used effectively for the simultaneous removal of both enantiomeric forms of various chiral pharmaceuticals from aqueous matrices. Full article

Gambling disorder (GD) constitutes a worldwide social and economic burden and is associated with impaired functioning and reduced quality of life. GD shares important mechanistic substrates with obsessive–compulsive disorder (OCD), including dysfunction of cortico-striato-thalamo-cortical circuitry and dysregulation of serotonergic pathways involved in impulsivity, compulsivity, and impaired inhibitory control. On this basis, selective serotonin reuptake inhibitors (SSRIs), widely used in several psychiatric disorders, have been investigated as potential pharmacological treatments for GD. Evidence concerning fluoxetine, fluvoxamine, paroxetine, sertraline, citalopram, and escitalopram is heterogeneous and overall limited. Some early single-blind, randomized, and open-label studies have reported reductions in gambling urges, severity, and compulsive symptoms. However, larger and more rigorous placebo-controlled trials have frequently failed to demonstrate consistent superiority over placebo. Interpretation of these findings is further limited by small sample sizes, short observation periods, high dropout rates, heterogeneous outcome measures, and substantial placebo response. While SSRIs remain biologically plausible candidates for modulating the compulsive and impulsive dimensions of GD, current evidence does not support their routine use as first-line pharmacological treatment. Their role appears most justified in the presence of psychiatric comorbidity or within individualized, phenotype-oriented treatment strategies. Full article

Background: The increasing consumption of psychoactive pharmaceuticals has led to their continuous release into aquatic environments. Methods: This study assessed the ecotoxicological responses, phytoremediation capacity, and ecological risk of seven psychoactive pharmaceuticals—citalopram (CIT), sertraline (SER), fluoxetine (FLU), alprazolam (ALP), clonazepam (CLO), risperidone (RIS), and topiramate (TOP)—using Lemna minor under controlled exposure conditions. Plants were exposed to a concentration gradient, and physiological endpoints, including relative growth rate, chlorophyll content, and maximum photosystem II efficiency (Fv/Fm), were evaluated alongside compound removal and abiotic degradation. Results: Dose–response modeling revealed substantial variability in toxicity, with TOP (EC₅₀ = 74.11 ng L⁻¹), CLO (104.8 ng L⁻¹), and RIS (138.5 ng L⁻¹) exhibiting the highest potency, whereas FLU (1751 ng L⁻¹), CIT (89,941 ng L⁻¹), and ALP (465,351 ng L⁻¹) were less toxic. Relative growth rate was the most sensitive endpoint. Mixture exposure did not result in additional toxicity compared to the most responsive individual compounds. Abiotic degradation was negligible for most compounds (<3%), except for SER (~42%) and FLU (~22%). In contrast, L. minor achieved net removal efficiencies of up to 81%, although reductions occurred under mixed conditions. Probabilistic risk assessment indicated a high ecological risk (msPAFtotal = 1.0), with RIS as the dominant contributor. Full article

Background: Data on early changes in body composition during acute-phase treatment in adolescents with major depressive disorder (MDD) remain limited. In particular, the utility of novel anthropometric indices reflecting central and visceral adiposity has not been explored in this population. This study therefore aimed to examine short-term clinical outcomes alongside detailed anthropometric measures in drug-naïve adolescent inpatients receiving fluoxetine-based pharmacotherapy. Methods: Prospective, clinician-directed, non-randomized inpatient study. Drug-naïve adolescents with severe MDD (n = 23) received fluoxetine 20 mg/day, with some patients additionally receiving low-dose quetiapine (100 mg/day) based on clinical indication for six weeks. Depressive symptomatology was evaluated by questionnaires Montgomery–Åsberg Depression Rating Scale (MADRS) and Children’s Depression Inventory (CDI). Conventional and novel anthropometric indices (BMI, WHtR; BRI, AVI, ABSI, BAI) were examined using the objective bioimpedance-derived method for body composition. Results: Depressive symptom severity decreased over the six-week treatment period, with significant improvements observed on both MADRS and CDI (time effect p < 0.001). Response and remission rates increased over time in the overall sample. No statistically significant changes were observed in conventional or novel anthropometric indices across the study period. Conclusions: In this prospective pilot cohort of adolescent inpatients with MDD, six weeks of fluoxetine-based pharmacotherapy was associated with improvement in depressive symptoms. No short-term changes were observed in anthropometric indices; however, given the small sample size and limited follow-up, these findings should be interpreted cautiously and cannot be considered definitive evidence of cardiometabolic safety. Full article

Mushroom use dates back to ancient times, and it currently remains significant among indigenous and urban populations as a medicinal option. Psilocybe species are suggested to modify emotions when administered in macro- or microdose form for the treatment of anxiety and depression, both often affected by a delayed onset and adverse effects of current pharmacological therapy. The objective of this study was to evaluate the anxiolytic and/or antidepressant-like effects of P. cubensis mushroom aqueous extract (PcAE) microdosing in mice using open-field and rota-rod tests, followed by plus-maze or forced swimming tests. We also evaluated changes in neuronal activity and dendritic maturation using electrocorticography (ECoG) and immunohistochemical techniques. The outcomes were compared with an effective macrodose of PcAE and antidepressant fluoxetine (FLX). For this study, mice were grouped as follows: (1) vehicle, (2) acute, and (3) repeated (10 days) PcAE microdosing (1 µg/kg); (4) single PcAE macrodose (1 g/kg); and (5) acute and (6) repeated reference drug fluoxetine (FLX, 10 mg/kg).The anxiolytic and antidepressant-like effects using microdosing were similar to those observed with macrodoses of PcAE and FLX; significant dose- and/or time-dependent changes in the ECoG and dendritic maturation of hippocampus neurons were also observed, in addition to altered corticosterone levels. To conclude, P. cubensis mushroom promotes brain effects in mice after micro- and macrodosing, supporting its potential as a therapeutic alternative for mental health. Full article

Objective: ZhiZhu Kuanzhong (ZZKZ) capsule, a Chinese herbal extract, is extensively employed for the clinical management of functional dyspepsia (FD) in China. This study aimed to elucidate the therapeutic efficacy and underlying mechanisms of ZZKZ on the co-morbidity of anxiety and depression of FD. Methods: The FD model was established in Sprague–Dawley rats via neonatal gastric irritation with 0.1% iodoacetamide. Subsequently, FD rats were gavaged with ZZKZ or fluoxetine. Depression-like behaviors were evaluated using the sucrose preference test (SPT) and forced swimming test (FST), while anxiety-like behaviors were assessed via light-dark box (LDB) and open field tests (OFTs). Network pharmacology and molecular docking were conducted to explore the mechanisms of ZZKZ’s action. Hippocampal levels of monoamine neurotransmitters and monoaminergic system components were evaluated by HPLC and RT-qPCR, respectively. Serum concentrations of HPA axis hormones were determined by ELISA. Results: ZZKZ administration reversed the deficits in body weight gain and food intake in FD rats. Behaviorally, ZZKZ increased sucrose consumption in SPT and prolonged swimming duration in FST, and it increased duration and entries into the central zone in OFT. According to the prediction of network pharmacology, ZZKZ treatment elevated hippocampal levels of 5-HT/NE/DA, increased expression of TPH2/TH, and decreased expression of MAO_A/SERT in FD rats. Molecular docking further confirmed high-affinity binding between core ingredients of ZZKZ and TPH2/TH/MAO_A/SERT. Moreover, ZZKZ administration attenuated the stress-induced elevation of serum CRH/ACTH/CORT. Conclusions: ZZKZ effectively ameliorates the disordered gut–brain interaction and mitigates anxiety-like and depression-like behaviors, which might be modulated by the hippocampal monoaminergic system and hypothalamic–pituitary–adrenal axis response. 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

Alzheimer’s disease (AD) is the most prevalent neurodegenerative disorder in the aging population. Drug repurposing provides a cost-effective strategy to identify novel therapeutics that may mitigate age-associated pathologies. Here, we report the therapeutic potential of fluoxetine, a selective serotonin reuptake inhibitor commonly used as an antidepressant, in alleviating cognitive impairment and AD-like pathology in 5xFAD mice, a transgenic model of familial AD. Chronic fluoxetine administration significantly ameliorated anxiety-like behavior and cognitive deficits in 5xFAD mice, as assessed by open field, Y-maze, and novel object recognition tests. Fluoxetine treatment was associated with reduced amyloid plaque deposition in the hippocampus and cortex, attenuation of microglial activation, and decreased expression of inflammatory cytokines. At the molecular level, fluoxetine increased phosphorylation of GSK3β at Ser9, which was associated with enhanced CREB phosphorylation and upregulation of the α-secretase ADAM10. These effects were further examined in SH-SY5Y neuronal cells, where CREB phosphorylation and ADAM10 expression were significantly modulated by GSK3β inhibition, whereas CaMKII inhibition had no detectable effect under our experimental conditions. Our findings suggest that fluoxetine modulates amyloid-associated signaling pathways in the 5xFAD model, in part through regulation of the GSK3β-CREB signaling framework. These results provide mechanistic insight into how fluoxetine may influence APP processing in an amyloid-driven pathological context, although further studies are required to clarify its translational implications in human AD. Full article

Sphingolipids (SL) are essential structural and bioactive components of cell membranes, remarkably involved in inflammatory signaling and membrane dynamics. Dysregulation of SL metabolism contributes to pathological inflammation and cellular stress. Selective serotonin reuptake inhibitors (SSRIs), such as fluoxetine (FXT), are known inhibitors of acid sphingomyelinase (aSMase), although their impact on macrophage SL remodeling and inflammatory responses remains unclear. Here, we investigated the modulation of FXT on SL species composition and inflammatory activation in THP-1-derived macrophages stimulated with inactivated SARS-CoV-2 particles, which is a model of viral-induced inflammation. Sphingolipidomic profiling revealed that FXT pre-treatment markedly reduced ceramide (Cer) species while increasing sphingomyelin (SM) and sphingosine-1-phosphate (S1P) levels, consistent with inhibition of the aSMase-Cer axis. These changes were accompanied by attenuation of proinflammatory components, including interleucin (IL)-6, IL-1β, and matrix metalloproteinase (MMP)-9, indicating that SL remodeling correlates with reduced macrophage activation. Despite pronounced alterations in membrane lipid composition, the quantification of extracellular vesicles (EVs) released by FXT-treated macrophages remained unchanged, however the EVs size distribution was smaller compared to non-treated cells. Altogether, our findings demonstrate that FXT reshapes SL metabolism and lipid membrane composition, thereby diminishing macrophage activation without affecting EVs biogenesis. This study emphasizes the immunometabolic role of SL on membrane reprogramming as a mechanism by which pharmacological aSMase inhibition modulates viral inflammation responses. Full article

Depression remains a major global health challenge, with a significant proportion of patients failing to respond to conventional antidepressants. This study aimed to evaluate the potential antidepressant effects and toxicological profile of a novel tetrodotoxin (TTX) oral film formulation in a mouse model of chronic unpredictable mild stress (CUMS). Male C57BL/6J mice were subjected to CUMS and treated daily with TTX oral film at doses of 10, 20, and 40 μg/kg, with fluoxetine (18 mg/kg) serving as a positive control. Behavioral assessments, including sucrose preference test, open field test, forced swimming test, elevated plus maze, and novel object recognition, demonstrated that TTX oral film administration alleviated depression- and anxiety-like behaviors and improved cognitive function. Furthermore, TTX oral film treatment restored hippocampal serotonin levels, which were depleted in CUMS mice, and showed no adverse effects on organ indexes after long-term use. Toxicological evaluation through acute toxicity testing revealed an oral LD₅₀ of 919 μg/kg, indicating a substantially improved safety profile compared to pure TTX and a wide therapeutic window. These findings suggest that the TTX oral film possesses significant antidepressant activity with favorable toxicological properties, supporting its potential as a novel and safe treatment for depression. Full article

This study investigates the effects of environmentally relevant concentrations of atrazine and fluoxetine, both individually and in combination, on aggressive behavior in male Betta splendens (B. splendens). Controlled behavioral assays were used to test the hypothesis that both individual and combined exposures would alter aggressive behavior, primarily by delaying the initiation of aggression and reducing the duration of specific displays. Twelve low-concentration (15 µg/L atrazine; 0.54 µg/L fluoxetine) and six high-concentration (30 µg/L atrazine; 1.08 µg/L fluoxetine) acute exposure trials were conducted. Latency to respond (LTR), broadside display (BSD), and frontal display (FD) were recorded over three days of male conspecific interactions. We analyzed the results using a negative binomial general linear model with day, atrazine, fluoxetine, and the interaction between the two compounds as predictors of the three behavioral responses. Results found that exposure to both compounds at either concentration significantly reduced aggressive behaviors compared to controls, increasing the latency to respond and decreasing broadside display and frontal display. For the low-concentration experiments, there were significant antagonistic effects from the interaction between fluoxetine and atrazine for all three behavioral responses (LTR p = 0.002, BSD p < 0.001, FD p < 0.001), with the combination of the two compounds showing a smaller impact than predicted by each singly. For the high-concentration experiments, there was a significant antagonistic interaction for BSD (p < 0.0001) and a marginally significant antagonistic interaction for LTR (p = 0.078). These findings suggest that these compounds can delay the onset and reduce the intensity of aggressive behaviors, underscoring the potential disruption of neurobehavioral pathways essential for survival, though the impact of these chemicals is altered by exposure conditions. This research highlights how environmental concentrations of common contaminants, especially in combination, may impair ecologically relevant behaviors in chemically impacted freshwater habitats. Full article

Despite the global increase in cat ownership, some cats exhibit owner-directed aggression, resulting in caregiver injury, infection, and anxiety. Severe cases are commonly treated with selective serotonin reuptake inhibitors such as fluoxetine; however, adverse effects, particularly transient anorexia, often discourage treatment initiation. Cannabidiol (CBD), a natural compound with reported anxiolytic properties and minimal anorexic effects, may represent an alternative therapy. This study aimed to characterise owner-directed feline aggression in Thailand, identify associated factors, and compare the efficacy of CBD with fluoxetine. Most caregivers were females aged 20–40 years, and most cats were neutered mixed-breeds aged 1–6 years living indoors in multi-human and multi-cat households. For demographic variables, only human–cat interactions (e.g., petting) were significantly associated with aggression. Handling-induced aggression was universal, with grooming as the most common trigger (56%). In a single-blind, 4–8-week trial, 100 cats were randomly assigned to control, CBD 1 mg/kg/day, CBD 2 mg/kg/day, fluoxetine 0.5–1 mg/kg/day, or combined CBD and fluoxetine. Aggression scores decreased significantly in all treatment groups compared with control (p < 0.05), with no differences among active treatments. CBD at 1 mg/kg/day showed efficacy comparable to fluoxetine without anorexic effects. Full article

Serotonergic signaling is traditionally conceived as a transient, vesicle-mediated process restricted to the synaptic cleft. Here, we propose an expanded model in which serotonin can also be inserted into the plasma membrane of neurons and glial cells, forming a stable, membrane-associated reservoir that prolongs its availability beyond classical synaptic timescales. In this framework, the synapse emerges not as a simple neurotransmitter–receptor interface but as a dynamic, multiscale medium where membrane order, hydration, and quantum-level processes jointly govern information flow. Two temporal “tunnels” appear to regulate serotonin bioavailability: its aggregation in synaptic vesicles during exocytosis, and its cholesterol-dependent insertion into neuronal and glial membranes at the tripartite synapse. Lipid raft microdomains enriched in cholesterol and gangliosides thus act as active regulators of a continuum between transient and constitutive serotonin signaling. This extended serotonergic persistence prompts a reconsideration of current pharmacological models and the action of antidepressants such as fluoxetine, which not only inhibits the serotonin transporter (SERT) but also accumulates in lipid rafts, perturbs raft organization, and alters serotonin–cholesterol equilibria, contributing to SERT-independent effects. Grounded in the recently established fundamental parameters of biological systems, this model invites a broader, quantum-informed rethinking of synaptic transmission. Full article

Background: Fluoxetine, a widely prescribed selective serotonin reuptake inhibitor, exhibits significant interindividual variability in pharmacokinetics, largely attributed to pharmacogenomic factors. Objectives: The study aimed to evaluate the impact of pharmacogenetics and clinical determinants on the dose-normalized fluoxetine/norfluoxetine metabolic ratio in patients undergoing fluoxetine therapy in routine clinical settings. Methods: Genotypes for CYP2D6, CYP2C9, and CYP2C19 genotypes were determined in 47 patients receiving fluoxetine therapy using TaqMan^® assays. Steady-state trough plasma concentrations of fluoxetine and norfluoxetine were measured using validated high-performance liquid chromatography methods. Log₁₀-transformed dose-normalized fluoxetine/norfluoxetine metabolic ratio (logMR) was compared across CYP2D6, CYP2C9, and CYP2C19 genotype-predicted metabolizer groups. Multivariate generalized linear modeling (GLM) was used to evaluate the independent effects of CYP genotypes and clinical covariates on the logMR. Results: The logMR differed significantly among the CYP2D6 genotype-predicted metabolizer groups (p < 0.003). CYP2D6 poor metabolizers exhibited significantly higher logMR than normal metabolizers (p < 0.004). The GLM analysis confirmed that CYP2D6 genotype was the only significant predictor of the logMR independent of all clinical covariates. No significant effects of CYP2C9, CYP2C19 genotypes, or clinical variables on the logMR were observed. Conclusions: These findings highlight CYP2D6 genotype as a key determinant of fluoxetine metabolism during standard treatment. No associations were observed with CYP2C9 or CYP2C19 genotypes or clinical factors. Full article

Fluoxetine (FLX) is an antidepressant pertaining to the class of selective serotonin reuptake inhibitors. FLX use has increased in the past decade culminating in its discharge to surface waters. Owing to the limited knowledge about the toxicity of this drug to aquatic biota, this study aimed to evaluate potential toxic effects of FLX on green algae Chlorella vulgaris, cyanobacteria Microcystis novacekii, marine bacteria Aliivibrio fischeri, and mollusk Biomphalaria glabrata. Assays with C. vulgaris and M. novacekii followed OECD protocol 201 (2011) and NBR 12648 standard (2018), respectively. The assay with A. fischeri was carried out according to ISO/OIN 11348-3 (2007). Toxicity assays with B. glabrata were performed by exposing these organisms (newborn and embryos) in 24-well culture plates for 3 and 7 days, respectively. All test-organisms were exposed to at least 6 different concentrations of FLX, ranging from 0.1 to 20,000 µg/L, in triplicates. Effect concentrations (EC50) obtained for these assays showed that FLX is more toxic to M. novacekii (10.71 ± 1.67 µg/L), followed by C. vulgaris (13.01 ± 2.01 µg/L) and A. fischeri (3140 ± 1050 µg/L). Regarding B. glabrata, the 50% lethal concentration for newborns was 1770 ± 260 µg/L, while for embryos it was equivalent to 34.98 ± 3.66 µg/L. Considering recent reports of FLX occurrence in environmental matrices in the µg/L range, results reported in this study and the toxicity classification criteria by the Globally Harmonized System, FLX poses high risk to aquatic environments, its biodiversity, and ecosystems. Therefore, measures must be taken to prevent the disposal of waste containing FLX into the environment, especially in region lacking basic sanitation infrastructure. Full article