Search Results (292)

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

Fluoxetine and carbamazepine are widely prescribed psychotropic drugs, yet few studies have quantified metal(loid) impurities in these medicines, which may pose health risks to patients. This study aimed to determine concentrations of As, Cd, Cr, Cu, Fe, K, Mg, Mn, P, Pb, Se, and Zn in brand, similar, and generic samples of fluoxetine and carbamazepine marketed in Campo Grande, Brazil. Drug samples were purchased from local pharmacies, digested with acid, and analyzed by Inductively Coupled Plasma Optical Emission Spectrometry (ICP OES). Results showed that arsenic was detected only in fluoxetine samples, with concentrations ranging from 0.068 to 0.217 mg/kg, all below national and international limits. Phosphorus presented the highest levels, especially in fluoxetine, reaching up to 14,000 mg/kg, and up to 93 mg/kg in carbamazepine. Other elements such as Fe (0.07–3.03 mg/kg), Mg (0.21–259 mg/kg), K (up to 45 mg/kg), Se (up to 1.5 mg/kg), and Zn (up to 4.2 mg/kg) were also quantified, while Cd, Cr, Cu, and Pb were below detection limits. The hazard index (HI) exceeded 1 for all carbamazepine samples and for one brand, two similar, and three generic fluoxetine samples, indicating that the intake of these medications may pose potential health concerns. These findings underscore the need for stricter monitoring of metal(loid) impurities in psychotropic drugs to protect patient safety and ensure regulatory compliance. Full article

The aim of this study was to evaluate the impact of fluoxetine, a widely used selective serotonin reuptake inhibitor, on two aquatic plants: Lemna minor and Spirodela polyrhiza. Additionally, the effect of exogenous serotonin on the level of fluoxetine-induced stress in duckweed will be studied. Increasing presence of antidepressants in surface waters poses ecological risks, and the duckweed species are ideal model organisms for ecotoxicological studies due to their rapid growth and ability to accumulate pollutants. For 14 days, plants were exposed to fluoxetine (0.001–150 mg L⁻¹), followed by a recovery phase in a drug-free medium or a medium supplemented with exogenous serotonin. We analysed morphological/physiological parameters (frond length and area, fresh and dry mass, hydration, stomatal size), the activity of antioxidant enzymes (catalase, ascorbate peroxidase, superoxide dismutase), cell viability, and the level of heat-shock proteins. The plants’ ability to remove fluoxetine from the medium was also assessed. High fluoxetine concentrations (50–150 mg L⁻¹) significantly reduced fresh mass (by 63–98% in L. minor and 56–97% in S. polyrhiza), frond area (by 21–48% in L. minor and 11–25% in S. polyrhiza), and cell viability (by 36–94% in L. minor and 49–94% in S. polyrhiza), and induced oxidative stress. Despite this, both species showed high regeneration potential after the stressor’s removal. Serotonin supplementation did not affect morphology but increased antioxidant enzyme activity, improved cell viability, and elevated heat-shock proteins levels. Crucially, serotonin significantly increased the efficiency of fluoxetine removal. The data can provide a basis for predicting fluoxetine removal efficiency in plants with different levels of endogenous serotonin. L. minor and S. polyrhiza exhibit substantial tolerance to fluoxetine, and antioxidative enzymes are sensitive markers of this stress. Full article

Background/Objectives: Interpersonal violence is an increasing public health concern, and its prediction and prevention remain global challenges. This study aimed to identify prescribed medications associated with interpersonal violence in Spain. Methods: A descriptive, longitudinal and retrospective study and case-non case study of spontaneous reports of adverse drug reactions corresponding to interpersonal violence recorded in the Spanish Pharmacovigilance Database (FEDRA^®) from 1984 to 31 March 2021. Results: 533 cases were reported in the study period. The mean age was 46.70 years with ages ranging from 1 to 99 years. There were no sex differences except in child and adolescent age group where most reports were from male. Main therapeutic groups involved were nervous system (62.3%), anti-infectives for systemic use (10%) and respiratory system (8.6%). Mostly drugs reported were montelukast, levetiracetam, bupropion, donepezil, perampanel, quetiapine, fluoxetine, and lorazepam. A statistically significant association/disproportion in the notification has been found in the reporting of interpersonal violence and different drugs according to the literature, notably atomoxetine, perampanel, memantine, donepezil, montelukast and methylphenidate. Conclusions: The results highlight that interpersonal violence, while rare, could occur as a clinically relevant adverse reaction to a small subset of medications. They underscore the importance of careful prescribing, especially in vulnerable populations and in individuals with a history of psychiatric disorders. Full article

Background: Thunbergia alata is employed in traditional medicine to treat culture-bound syndromes such as “susto” (fright) or “espanto” (fearfulness). These conditions may correlate with depressive disorders. However, there is no evidence that this species has antidepressant properties. Aims: To characterize the antidepressant-like effect of an aqueous extract of T. alata in different paradigms and to analyze the role of brain monoamines in such actions. Methods: Independent groups of mice were treated with saline or the extract (1, 5, 10, 50, and 100 mg/kg; p.o.) and evaluated in the tail suspension (TST) and forced swimming tests (FST). Biochemical mechanisms were analyzed using inhibitors of monoamine synthesis, ligands of serotonergic receptors, and in vitro assays of MAO-A and MAO-B activity. Acute and sub-acute toxicity was evaluated. Results: The extract significantly reduced the immobility time of mice in both the TST and the FST, without affecting locomotor activity, as did the prototypical antidepressant desipramine. PCPA, AMPT, and NAN-190 abolished the extract’s effects on despair, while serotonergic ligands (8-OH-DPAT, fluoxetine, and pindolol) facilitated their antidepressant action. T. alata inhibited MAO-A and B activity. High doses of the extract produced no change in organ morphology; LD₅₀ was >2000 mg/kg. Conclusions: This is the first study to demonstrate that an aqueous extract of T. alata produces antidepressant effects mediated by the monoamine brain levels, especially serotonin. In addition to its use in culture-bounded syndromes, the present findings of safety and efficacy give support to the proposal that T. alata may be used in the treatment of depression. Full article

Freshwater planarians are an emerging model for toxicology and neuroscience because of their amenability to rapid behavioral screening and remarkable ability to regenerate a cephalized nervous system. As invertebrates, planarians can help reduce the use of vertebrates in research; however, laboratories typically maintain planarians on diets of homogenized organic beef or chicken liver, raising ethical concerns with feeding a vertebrate diet. Organic liver is difficult to obtain, and preparation methods vary, introducing intra- and interlaboratory variability. Here, we show that Dugesia japonica planarians can be maintained for over a year on commercially available red midge larvae (RML), a natural prey of freshwater planarians. We found only minor effects on reproduction and gene expression. To explore dietary effects on behavior and chemical sensitivity, we compared the results of a chemical screen using dimethyl sulfoxide, diazinon, and fluoxetine on adult and regenerating D. japonica. We found that differences in potency and bioactivity for planarians on liver and RML diets were on par with inter-experiment variability of planarians fed the same diet. We also show that RNA interference is feasible with RML. Because RML requires no preparation and sustains planarian populations long-term, this invertebrate diet can substitute liver and help reduce the use of vertebrates in research. Full article

Background/Objective: Serotonin and dopamine are key neurotransmitters involved in regulating mood, anxiety, and locomotor activity. Specific transporters mediate their reuptake, SERT and DAT, making them targets for drugs such as Fluoxetine and Methylphenidate. Zebrafish (Danio rerio), due to their genetic and neurochemical similarity to humans, serve as a valuable model for studying the behavioral effects of these drugs. This study aimed to compare the behavioral phenotypes induced by SERT and DAT blockers in adult zebrafish using the Novel Tank Diving Test (NTT), thereby generating a swimming profile for drugs acting on these monoamine transporters that can be utilized in drug discovery and behavior. Methods: Adult zebrafish were administered Fluoxetine or Methylphenidate and subjected to the NTT. Behavioral endpoints measured included bottom-dwelling time (anxiety-like behavior), swimming velocity (locomotor activity), and transitions to the upper zone (exploratory behavior). Results: Fluoxetine treatment significantly reduced bottom-dwelling behavior, increased transitions to the upper zone, and decreased erratic swimming, indicating reduced anxiety and enhanced exploration. In contrast, Methylphenidate administration led to prolonged bottom-dwelling and reduced exploration, suggesting increased anxiety-like behavior and decreased exploration. These findings highlight distinct behavioral profiles resulting from selective modulation of serotonergic and dopaminergic pathways. Conclusions: The study demonstrates that SERT and DAT blockades produce divergent behavioral effects in adult zebrafish, with Fluoxetine exhibiting anxiolytic and exploratory-promoting actions. At the same time, Methylphenidate induces anxiety-like and less exploratory behaviors. These results underscore the utility of zebrafish as a valuable translational model for neuropharmacological research and drug discovery, providing insights into the differential impact of serotonergic and dopaminergic modulation on behavior. Full article

Background/Objectives: Parkinson’s disease (PD) is the second most common neurodegenerative disease (NDD), marked by the progressive loss of dopaminergic neurons in the substantia nigra that causes motor dysfunction. Growing evidence indicates that neuroinflammation plays a crucial role in the onset and progression of PD, though the exact mechanisms are still unclear. In this study, we examined the anti-inflammatory and neuroprotective effects of 4-[3-oxo-3-(2-trifluoromethyl-phenyl)-propyl]-morpholinium chloride (OTPM), a fluoxetine derivative and selective serotonin reuptake inhibitor, in both lipopolysaccharide (LPS)-stimulated BV-2 microglial cells and an MPTP-induced mouse model of PD. Methods: C57BL/6 mice were orally administered OTPM (10 mg/kg b.w.) for 7 days and intraperitoneally injected with MPTP (20 mg/kg b.w.) for one day, with four injections at 2 h intervals. Bradykinesia was assessed using the Y-maze and Pole tests. Protein and mRNA levels were examined in vitro and in vivo using Western blotting and RT-PCR. Immunofluorescence was used to assess microglial and astrocyte activation. Results: In vitro, OTPM significantly decreased nitric oxide (NO) production (p < 0.001) and suppressed the protein and mRNA expression of iNOS (p < 0.001), COX-2 (p < 0.001), and pro-inflammatory cytokines, including IL-β (p < 0.001), IL-6 (p < 0.001), and TNF-α (p < 0.01), in LPS-activated BV-2 microglia. Further mechanistic studies showed that OTPM inhibited NF-κB phosphorylation and blocked its nuclear translocation, thereby reducing inflammatory signaling. In vivo, treatment with OTPM (10 mg/kg for 7 days) significantly reduced the MPTP-induced activation of microglia (MAC-1) and astroglia (GFAP) in the brain and improved behavioral deficits associated with PD, as assessed in the Y-maze and pole tests. Conclusions: Overall, these results reveal that OTPM has strong anti-neuroinflammatory and neuroprotective properties, suggesting its potential as a new therapeutic candidate for PD and other disorders associated with neuroinflammation. Full article

Background: Fluoxetine is widely prescribed to treat depression but exhibits high inter-individual and inter-ethnic pharmacokinetic (PK) variability. Most published population pharmacokinetic (PopPK) models were derived from Western patients, and their applicability to Chinese patients remains uncertain. Methods: A systematic review of the published fluoxetine PopPK models was carried, and the relevant demographic and model parameters were extracted. A retrospective real-world dataset from Chinese psychiatric patients was then collected. External evaluation was conducted to assess the model’s predictive performance. Subsequently, a joint parent–metabolite PopPK model was developed to better characterize fluoxetine and its active metabolite norfluoxetine in Chinese patients. Finally, Monte Carlo simulations were performed to evaluate once-daily dosing regimens of 10–60 mg for 30 days, focusing on the probability of achieving target (PTA) steady-state trough concentrations (C_min,ss). Results: Two published PopPK models were identified and externally evaluated using data from 198 Chinese patients with 241 fluoxetine and 241 norfluoxetine plasma concentrations. Both models were shown to have prediction discrepancy. The parent drug–metabolite model was used to describe the characteristics of fluoxetine and norfluoxetine in the Chinese population. Sex was identified as the significant covariate, and males exhibited a 16.5% higher clearance than females. The simulation results indicate that the maximum effective dose for females is 30 mg once daily, and for males, it is 40 mg once daily. Conclusions: This study provides the first comprehensive external evaluation of published fluoxetine PopPK models and establishes a tailored joint model that incorporates sex effects to explain trough variability in Chinese psychiatric patients. The findings support 30–40 mg once daily as a practical dosing range for Chinese adults and adolescents, with males more likely to require the higher dose. Full article

Background: Aromatic plants like peppermint (Mentha x piperita, Lamiaceae) have a long tradition of use. Most of the plant material is used to produce herbal drugs and for the isolation of essential oils. However, since essential oils are present in very small amounts, the largest proportion of plants remains unused. Objectives: The aims of this study were the analysis of chemical, biochemical, antimicrobial, and pharmacological properties of peppermint waste material extracts (derived from stems, post-distillation waste, and deodorized leaves) in comparison with the officially prepared extract. Results: The obtained results revealed that the investigated peppermint waste extracts (PWEs) are a rich source of phenolic compounds, where rosmarinic acid was determined as the dominant one (7.05–21.19 mg/g d.e.). Antioxidant potential and hepatoprotective effect of PWE were comparable with the official extract, where the most active ones were those prepared by treating the deodorized leaves with both 45% and 75% ethanol. In addition, PWE exhibited notable antimicrobial and anticholinesterase activity. Results of pharmacological studies on experimental animals showed that peppermint extracts (official and those made from deodorized leaves) did not interfere with the effect of the tested drugs, midazolam and fluoxetine. The examined extracts neither exerted an influence on motor coordination nor acted as antidepressants. Results of the elevated plus maze test indicated that PWE affected the activity of the central nervous system. Conclusions: PWEs represent a significant source of phenolic compounds, especially rosmarinic acid, and they can be used in the pharmaceutical industry to produce various herbal products and in the food industry as natural additives. Full article

Depression is a common mental disorder during gestation, posing potential risks to fetal development and leading to behavioral and psychiatric alterations in offspring. Pharmacological intervention, particularly with selective serotonin reuptake inhibitors (SSRIs), is often necessary. This study investigated the effects of fluoxetine (F) on behavioral and memory changes in rodent offspring following maternal gestational and lactation treatment, as well as potential alterations in hippocampal cellularity compared to control (C) progeny. Methodologies included the Morris water maze, elevated plus maze, activity monitoring, parental behavior assessments, and isotropic fractionation for the quantification of hippocampal cells and neurons. Results indicated that maternal fluoxetine exposure significantly affected the body mass, brain weight, and hippocampal metrics of the offspring, aligning with the ‘selfish brain’ hypothesis. Notably, dams treated with fluoxetine showed reduced parental care, leading to offspring with increased activity levels but no changes in anxiety-like behaviors. However, while there was a decline in learning and memory retention, as assessed by the Morris water maze, working and reference memory did not differ significantly from those of controls. This study establishes an association between fluoxetine treatment, increased hippocampal neuron density, and behavioral changes related to memory and hyperactivity, with implications for understanding behavioral disorders and informing future therapeutic interventions. Full article

Background: Selective serotonin reuptake inhibitors (SSRIs) are widely prescribed, yet their direct impact on ovarian function remains poorly understood. While serotonin signaling is known to occur within the ovarian follicle, the specific molecular consequences of its disruption by SSRIs are unclear. This study aimed to elucidate the direct, intra-ovarian mechanisms by which fluoxetine, a common SSRI, affects follicular development and oocyte competence. Methods: We administered fluoxetine (20 mg/kg) or vehicle daily for seven days to both prepubertal and adult female mice to model short-term therapeutic exposure. Results: Fluoxetine treatment successfully blocked peripheral serotonin uptake, reducing serum levels by over 90%. Crucially, this occurred without altering circulating levels of estradiol, FSH, or LH and without disrupting the estrous cycle, indicating a mechanism independent of the central hypothalamic–pituitary–gonadal axis. Instead, we pinpoint a direct ovarian effect: fluoxetine inhibited serotonin transport activity in oocytes and significantly downregulated the expression of the pivotal oocyte-derived growth factor Gdf9. This was accompanied by reduced expression of genes crucial for granulosa cell function (Lhr, Fshr) and steroidogenesis (Cyp19a1). Functionally, these molecular changes manifested as a decline in oocyte quality and a significant reduction in ovulation rates in adult mice. Notably, these detrimental effects were more pronounced in prepubertal mice, indicating a heightened vulnerability during early follicular development. Conclusions: Our findings reveal a direct, intra-ovarian mechanism of fluoxetine-induced disruption. By inhibiting oocyte serotonin transport and downregulating GDF9, fluoxetine impairs critical oocyte–granulosa cell communication, thereby compromising oocyte competence and reducing fertility outcomes. This work identifies follicular development as a critical window of susceptibility to SSRI exposure, holding significant clinical implications for reproductive-aged and adolescent populations. Full article

Hearing loss and serotonergic dysfunction both impact social and cognitive behaviors, yet their neurobiological interplay remains poorly understood. This study investigated whether perinatal fluoxetine exposure alters myelination in (auditory) brain regions during development. Female Wistar rats received 10 mg/kg fluoxetine from gestational day 1 until postnatal day (PND)21. Brain tissue was collected from male offspring at PND21 and PND35. Myelination was assessed via immunohistochemical analysis of Myelin-Associated Glycoprotein (MAG) and Myelin Basic Protein (MBP) in the auditory cortex, inferior colliculus, and corpus callosum. MAG+ cell counts, MBP+ area, and MBP fluorescence intensity were quantified. No major effects of fluoxetine were observed on myelin markers in any brain region or developmental stage. However, changes in myelination emerged between PND21 and PND35. MAG+ cell density declined in the inferior colliculus but remained stable in the auditory cortex. MBP+ area decreased over time in both the corpus callosum and auditory cortex, while MBP fluorescence intensity increased in the corpus callosum. These results suggest that myelination changes between PND21 and PND35 are region- and age-dependent and not altered by fluoxetine. These findings highlight the dynamic nature of postnatal myelination and suggest that serotonergic alterations alone may be insufficient to disrupt structural maturation in auditory regions. Full article

Pharmaceuticals can be found in the aquatic environment and cause unwanted effects on organisms. The present work aimed to characterize the toxic mode of action of the antidepressant fluoxetine (FLX) on the freshwater microalga Raphidocelis subcapitata. With this aim, the microalga was exposed to low levels (µg/L) of FLX for 72 h. Exposure to 20–30 µg/L FLX arrested algal growth, which can be explained by the blockage of algal nuclear division. In addition, FLX (15–30 µg/L) deeply altered the alga’s metabolism, which was reflected by an increase in esterase activity, mitochondrial dysfunction (hyperpolarization of inner mitochondrial membrane), and reduction in the content of photosynthetic pigments: chlorophyll a (chla) and carotenoids (car). A sharp decline in photosynthetic performance, revealed by the reduction in maximum photochemical quantum yield (F_v/F_m), effective photochemical quantum yield (ΦPSII), and photosynthetic electron transport rate (ETR) of photosystem II (PSII), was also observed. FLX, at 30 µg/L, induced the intracellular accumulation of reactive oxygen species (ROS) and lipid peroxidation, with a marginal loss (1%) of cell membrane integrity. The results presented here contribute to the elucidation of the toxic mode of action of FLX on the microalgae R. subcapitata and, simultaneously, warn of the negative impact of the presence of pharmaceutical compounds in freshwater aquatic environments. Full article