Foodborne fluoxetine impacts the immune response in rainbow trout (Oncorhynchus mykkis).

The aim of this study was to reveal the effects of foodborne fluoxetine on morphological and condition profile, hematological profile, biochemical and oxidative stress indices on juvenile rainbow trout. The study was performed according to OECD Guideline No. 215. Fluoxetine was incorporated into Biomar 921 pellets at a dose of 0.047 mg/kg (environmental concentration), 0.577 mg/kg and 6.7 mg/kg. There was statistically significant change in hematological profile, including an increasing trend in neutrophil/lymphocyte ratio and a decreasing trend in the number of lymphocytes. Measurements of oxidative stress indicated decreased activity of the detoxifying enzyme glutathione-S-transferase in the liver and kidney. However, the measurement of GR, GPx, CAT, SOD activity, and TBARS showed no changes. Histopathological examination revealed damage to the proximal tubules of caudal kidney in exposed groups. This study confirms that fluoxetine has a significant effect on immune response.

Tianeptine, but not fluoxetine, decreases avoidant behavior in a mouse model of early developmental exposure to fluoxetine.

Depression and anxiety, two of the most common mental health disorders, share common symptoms and treatments. Most pharmacological agents available to treat these disorders target monoamine systems. Currently, finding the most effective treatment for an individual is a process of trial and error. To better understand how disease etiology may predict treatment response, we studied mice exposed developmentally to the selective serotonin reuptake inhibitor (SSRI) fluoxetine (FLX). These mice show the murine equivalent of anxiety- and depression-like symptoms in adulthood and here we report that these mice are also behaviorally resistant to the antidepressant-like effects of adult SSRI administration. We investigated whether tianeptine (TIA), which exerts its therapeutic effects through agonism of the mu-opioid receptor instead of targeting monoaminergic systems, would be more effective in this model. We found that C57BL/6J pups exposed to FLX from postnatal day 2 to 11 (PNFLX, the mouse equivalent in terms of brain development to the human third trimester) showed increased avoidant behaviors as adults that failed to improve, or were even exacerbated, by chronic SSRI treatment. By contrast, avoidant behaviors in these same mice were drastically improved following chronic treatment with TIA. Overall, this demonstrates that TIA may be a promising alternative treatment for patients that fail to respond to typical antidepressants, especially in patients whose serotonergic system has been altered by in utero exposure to SSRIs.

Prenatal fluoxetine impairs non-hippocampal but not hippocampal memory in adult male rat offspring.

Fluoxetine is often prescribed to treat depression during pregnancy. Rodent studies have shown that fluoxetine exposure during early development can induce persistent changes in the emotional behavior of the offspring. However, the effects of prenatal fluoxetine on memory have not been elucidated. This study evaluates the memory of adult male offspring from rat dams orally administered with a clinically relevant dose of 0.7 mg/kg fluoxetine from 9 weeks before pregnancy to 1 week before delivery. Hippocampal-dependent (Morris Water Maze, MWM) and non-hippocampal-dependent (Novel Object Recognition, NOR) memory paradigms were assessed. Anxiety- and depressive-like symptoms were also evaluated using the Open Field Test, Tail Suspension Test and Sucrose Preference Test. Male rats exposed to fluoxetine during gestation displayed NOR memory impairments during adulthood, as well as increased anxiety- and depressive-like symptoms. In the MWM, the offspring of fluoxetine-treated dams did not show learning deficits. However, a retention impairment was found on remote memory, 15 days after the end of training. Molecular analyses showed increased expression of NMDA subunit NR2B, and a decrease in NR2A-to- NR2B ratio in the temporal cortex, but not in the hippocampus, suggesting changes in NMDA receptor composition. These results suggest that in utero exposure to fluoxetine induces detrimental effects on non-hippocampal memory and in remote retention of hippocampal-dependent memory, which is believed to be stored in the temporal cortex, possibly due to changes in cortical NMDA receptor subunit stoichiometry. The present results warrant the need for studies on potential remote memory deficits in human offspring exposed to fluoxetine in utero.

Transcriptional analyses reveal different mechanism of toxicity for a chronic exposure to fluoxetine and venlafaxine on the brain of the marine fish Dicentrarchrus labrax.

Selective serotonin reuptake inhibitor (SSRI) and serotonin norepinephrine reuptake inhibitor (SNRI) are prescribed for clinical depression and detected in aquatic ecosystems. The main aim of this study was to explore and evaluate transcriptional responses of neurotransmitter genes in the brain of a marine fish species, European seabass, and to analyze global brain transcriptomic changes by a RNA-seq technology (MACE, massive analysis of cDNA ends). The juveniles were exposed to two psychopharmaceuticals: (i) fluoxetine (FLX) at the concentration of 0.5 µg/L and 50 µg/L; (ii) venlafaxine (VENX) at the concentration of 0.01 µg/L and 1 µg/L. The exposures were performed for 21 days, followed by a 7-day recovery period to assess the reversibility of effects. Both psychopharmaceuticals affected differentially the neurotransmitter mRNA expression analyzed by RT-qPCR (serotonin receptors: 5-ht3a, 5-ht3b; dopamine receptors: d2, d3; neurotransmitter transporter: sert, vmat; degrading enzyme: mao). Transcriptomic analyses after 21 days of exposure revealed 689 and 632 significant different transcripts by FLX at 0.5 and 50 µg/L, respectively, and 432 and 1250 by VENX at 0.01 and 1 µg/L, respectively, and confirmed different mechanism of toxicity between both compounds. At environmental concentrations, more general pathways including energy metabolism were affected, while at the higher concentration effects on neurotransmitter pathways were observed (FLX: exocytosis and vesicle formation; VENX: small molecule catabolism regulating dopamine and tyrosine level). These results provided new insights into the chronic effects of psychopharmaceutical compounds on marine fish and suggest the need of a separate ecotoxicological risk analysis.

Environmental level of the antidepressant venlafaxine induces behavioral disorders through cortisol in zebrafish larvae (Danio rerio).

Psychoactive drugs discharged into the environment have different effects on the behavior of vertebrates. The objective of this study was to evaluate the effect of venlafaxine on the behavior of zebrafish, and whether melatonin could reverse the induction of venlafaxine. In this study, a series of venlafaxine concentrations (1 µg/L, 10 µg/L, 100 µg/L) was used to treat zebrafish embryos from 2 hours post-fertilization (hpf) to 5dpf. We found that venlafaxine (1 µg/L) can stimulate the growth of the head area, eye area, and body length of zebrafish. The light-dark test showed that venlafaxine (1 µg/L) could increase the activity of zebrafish larvae. What's more, venlafaxine (1 µg/L) upregulated the expression of steroid regulatory factors including steroidogenic acute regulatory protein (star), cytochrome P450 family member 11A1 (cyp11a1) and 11 ß hydroxylase (cyp11b1) by cAMP-pCREB pathway, affecting the function of the steroidogenic cells, which might be involved in the increased cortisol levels in zebrafish larvae. Whereas, melatonin (230 µg/L) restored the altered locomotion behavior induced by venlafaxine and recovered the altered gene expression. Our results demonstrate that venlafaxine at levels detected in the aquatic environment impacts behavior and may compromise the adaptive responses to the environment in zebrafish larvae.

Demonstration of an action pathway in mouse platelets leading to prolongation of bleeding time by fluoxetine.

Fluoxetine is one of SSRIs commonly used as first-line antidepressants. It also induces adverse effects, including bleeding events. This study clarified the bleeding effect of fluoxetine and explored the action cascade of this drug leading to a longer bleeding time. A total of 48 male adult mice were evenly distributed into four groups and given fluoxetine in saline at 0, 4, 8, or 16 mg/kg, for 14 days. On day 15, tail bleeding time of 6 mice/group was measured, and their blood samples were collected for analyses of relevant platelet functions. The remained mice were allowed to survive for another 14 days without fluoxetine, and subjected to the same analyses on day 29. A significant effect of fluoxetine was reveled on bleeding time (F (3,20) = 16.842, P < 0.01) and intraplatelet serotonin (F (3,20) = 90.967, P < 0.01). Moreover, fluoxetine effectively inhibited platelet aggregation (F(3, 20) = 30.247, P < 0.01), decreased amount of GPIbα (F(3, 20) = 23.855, P < 0.01), suppressed GPIIb/IIIa activation (F(3, 20) = 89.441, P < 0.01), and lowered P-selectin (F(3, 20) = 7.960, P < 0.01) on platelet surface. Negative correlations existed between bleeding time and the aforementioned four indices, whereas correlations between intraplatelet serotonin and the same indices were positive. All changes returned to same levels as Control group after fluoxetine withdrawal. These data suggest an action pathway of fluoxetine starting at binding to serotonin transporter, followed by decreased intraplatelet serotonin, increased GPIbα shedding, suppressed GPIIb/IIIa activation, and inhibited α-granule release, and concluding with prolonged bleeding time in mice.

Fluoxetine chronic exposure affects growth, behavior and tissue structure of zebrafish.

Fluoxetine (FLX) is among the top 100 pharmaceutical prescribed annually worldwide and consequently is often detected in wastewater treatment plant effluent and surface waters, in concentrations up to 2.7 and 0.33 µg/L, respectively. Despite the presence of FLX in surface waters, little is known about its chronic effects in fish. Thus, this study aimed at investigating the chronic toxicity of FLX to Danio rerio adults. Rate of weight gain, behavior (feeding and swimming activity) and tissue organization (liver and intestine) were evaluated, after 30 days exposure. A lower rate of weight gain was observed at 100 µg/L FLX. The food intake time decreased, showing a decrease in fish appetite. The preference for the upper aquarium layer was observed at 10 and 100 µg/L of FLX, indicating an inhibition of the stress level (anxiolytic effect). Mild to moderate damage of hepatic tissue and a decrease epithelium height and increase in villus height of intestine were observed in fish exposed to concentrations as low as 0.01 µg/L. Based on obtained results, chronic exposure of fish to FLX could affect swimming and feeding behavior and alter morphological structure of liver and intestine tissues at environmental levels.

Differential effects of fluoxetine and venlafaxine in the neural embryonic stem cell test (ESTn) revealed by a cell lineage map.

There is a need for in vitro tests for the evaluation of chemicals and pharmaceuticals that may cause developmental neurotoxicity (DNT) in humans. The neural embryonic stem cell test (ESTn) is such an in vitro test that mimics early neural differentiation. The aim of this study was to define the biological domain of ESTn based on the expression of selective markers for certain cell types, and to investigate the effects of two antidepressants, fluoxetine (FLX) and venlafaxine (VNX), on neural differentiation. A cell lineage map was made to track neural differentiation and the effects of FLX and VNX in ESTn. Whole transcriptome analysis revealed differentiation from an embryonic stem cell population to a mixed culture of neural progenitors, neurons and neural crest cells 7 days into differentiation. Maturing neurons, astrocytes and oligodendrocytes were present after 13 days. Exposure to FLX or VNX led to different expression patterns between compounds at both time points. On day 7, both compounds upregulated most of the stem cell- and immature neuron markers, but had distinct effects on neural subtype markers. FLX downregulated glycinergic markers and upregulated cholinergic markers, while VNX had the opposite effect. On day 13, FLX and VNX affected their specific therapeutic targets, represented by mainly serotonergic markers by FLX- and dopaminergic and noradrenergic markers in VNX-exposed cultures, as well as oligodendrocyte and glycinergic neuron markers. This proof of concept study shows the added value of assessing DNT in ESTn through a cell lineage map and gives mechanistic insight in the potential neurodevelopmental effects of FLX and VNX. More compounds should be tested to further evaluate the use of the cell lineage map.

Cortisol disruption and transgenerational alteration in the expression of stress-related genes in zebrafish larvae following fluoxetine exposure.

Fluoxetine (FLX), the active ingredient in well-known therapeutic drugs such as Prozac, is highly prescribed worldwide to treat affective disorders even among pregnant women and adolescents. Given that FLX readily crosses the placenta, a fetus from a treated pregnant woman is potentially at risk from unintended effects of the chemical. Moreover, FLX reaches aquatic ecosystems at biologically active levels through sewage release, so fish may also be inadvertently affected. We previously demonstrated that FLX exposure to environmentally- (Low FLX Lineage; LFL) and human- (High FLX Lineage; HFL) relevant concentrations during the first 6 days of life in zebrafish (ZF; Danio rerio) reduced cortisol levels in the adults (F0), an effect that persisted across 3 consecutive unexposed generations (F1 to F3). Here, we show that the transcriptional profile of selected genes in the steroidogenesis pathway in the F0 whole-larvae varied in magnitude and direction in both FLX lineages, despite the same attenuated cortisol phenotype induced by both concentrations. We also observed an up-regulation in the transcript levels of some steroidogenic-related genes and a down-regulation of a gene involved in the inactivation of cortisol in the F3 HFL larvae. These findings on the transcript levels of the selected genes in the larvae from F0 and F3 suggest that specific coping mechanism(s) are activated in descendants to attempt to counteract the disruptive effects of FLX. Our data are cause for concern, given the increasing prescription rates of FLX and other antidepressants, and the potential long-term negative impacts on humans and aquatic organisms.

Orange peels modulate antioxidant markers and key enzymes relevant to erection in the penile tissue of paroxetine-treated rats.

In comparison to other antidepressant drugs, erectile dysfunction (ED) is more pronounced in paroxetine use. On the other hand, orange (Citrus sinensis) peels commonly consumed in various forms are used in folkloric medicine for ED management. Thus, this study evaluated the effect of orange peels infusion on sexual behaviour, nitric oxide (NO) level and some enzymes (arginase, phosphodiesterase-5 [PDE-5], acetylcholinesterase [AChE] and adenosine deaminase [ADA]) in paroxetine-treated rats. Erectile dysfunction was induced with paroxetine (10 mg/kg body weight). The animals were grouped into five (n = 6): normal rats; paroxetine-induced rats; paroxetine-induced rats treated with sildenafil citrate (5 mg/kg); paroxetine-induced rats treated with orange peels infusion (50 mg/kg); Paroxetine induced rats treated with orange peel infusions (100 mg/kg). The results revealed a significant decrease in sexual behaviour, NO level and the activities of antioxidant enzymes, while there was a significant increase in arginase, PDE-5, AChE and ADA activities in paroxetine-induced rats. However, orange peel infusions ameliorated erectile dysfunction in paroxetine-treated rats. This study showed some possible biochemical basis underlying the use of orange peels infusion in erectile dysfunction management.

Toxicity of Bupropion Overdose Compared With Selective Serotonin Reuptake Inhibitors.

OBJECTIVES: Adolescent depression and attempted and completed suicide are increasing in the United States. Because suicide is often impulsive, the means of self-harm are frequently items of convenience like medication. Authors of a recent study compared tricyclic antidepressant overdose to bupropion overdose. Fluoxetine and escitalopram are the only agents with Food and Drug Administration approval for pediatric depression, but off-label bupropion prescriptions are common. We sought to compare the effects of selective serotonin reuptake inhibitors (SSRIs) and bupropion in overdose. METHODS: This was an analysis of the National Poison Data System from June 2013 through December 2017 for adolescent (ages 10-19) exposures to SSRIs or bupropion coded as "suspected suicide." Demographics, clinical effects, therapies, and medical outcome were analyzed. RESULTS: There were 30 026 cases during the study period. Sertraline and fluoxetine accounted for nearly 60%, whereas bupropion was reported in 11.7%. Bupropion exposure was significantly associated with death (0.23% vs 0%; P < .001) or serious outcome (58.1% vs 19%; P < .001) as well as the 10 most common clinical effects, including seizures (27.0% vs 8.5%; P < .001) and hallucinations (28.6% vs 4.3%; P < .001). Bupropion exposure was significantly associated with the need for cardiopulmonary resuscitation (0.51% vs 0.01%; P < .001), intubation (4.9% vs 0.3%; P < .001), vasopressors (1.1% vs 0.2%; P < .001), and benzodiazepines (34.2% vs 5.5%; P < .001). There was a significant increase in all exposures and in proportion of serious outcomes over time. CONCLUSIONS: Adolescents who attempt self-harm are at higher risk for serious morbidity and poor outcomes with bupropion than with SSRIs. These risks, and the patient's propensity for self-harm, should be evaluated when therapy with bupropion is considered.

Assessment of trazodone-induced cardiotoxicity after repeated doses in rats.

Trazodone (TRZ) is an antidepressant drug commonly used in the treatment of depression, anxiety, and insomnia. Although some studies demonstrated the adverse effects of TRZ related to cardiovascular system, the conflicting results were observed in these studies. Therefore, we aimed to investigate the cardiac adverse effects of TRZ in rats at repeated doses in our study. In accordance with this purpose, TRZ was administered orally to rats at 5, 10, and 20 mg/kg doses for 28 days. Electrocardiogram records, serum aspartate aminotransferase (AST), lactate dehydrogenase, creatine kinase-myoglobin band, cardiac troponin-T (cTn-T) levels, DNA damage in cardiomyocytes, and histologic view of heart tissues were evaluated. In addition, glutathione (GSH) and malondialdehyde (MDA) levels were measured to determine the oxidative status of cardiac tissue after TRZ administration. Heart rate was decreased, PR interval was prolonged, and QRS and T amplitudes were decreased in 20 mg/kg TRZ-administered group compared to the control group. Serum AST and cTn-T levels were significantly increased in 10 and 20 mg/kg TRZ-administered rats with respect to control rats. DNA damage was significantly increased in these groups. Additionally, degenerative histopathologic findings were observed in TRZ-administered groups. Although there was no difference in MDA levels between groups, GSH levels were significantly decreased in 10 and 20 mg/kg TRZ-administered groups compared to the control group. Our results have shown that TRZ induced cardiotoxicity in rats dose-dependently. It is assumed that oxidative stress related to GSH depletion may be accompanied by these adverse effects.

Transformation products of citalopram: Identification, wastewater analysis and in silico toxicological assessment.

The objective of this study was to identify transformation products (TPs) of citalopram (CIT), an antidepressant drug, in laboratory experiments. Moreover, toxicity predictions and analyzes in wastewater samples were performed. For the formation of TPs, raw water was used for the processes of hydrolysis; photodegradation under ultraviolet (UV) irradiation and chlorination. The toxicities were predicted by computational toxicity assessment. The TPs were identified by liquid chromatography quadrupole time-of-flight mass spectrometry (LC-QTOF/MS) in broadband collision induced dissociation (bbCID) acquisition mode and product ion scan mode (MS/MS). The probable structures of the TPs under study were established based on accurate mass, fragmentations observed in the MS spectra and prediction tools software. The experiments resulted in seventeen possible identified TPs and their stability and formation was monitored over time in the experiments. Two of these TPs were identified in wastewater samples It was also observed that most of TPs formed were either less toxic then CIT or had a similar toxicity.

Bilateral sciatic neuropathy with severe rhabdomyolysis following venlafaxine overdose: A case report.

RATIONALE: Venlafaxine is an antidepressant and anxiolytic agent that functions by inhibiting central serotonin and norepinephrine reuptake, and it is a relatively recently introduced drug. In particular, overdose of venlafaxine has been reported to cause severe cardiac toxicity including ventricular tachycardia, prolongation of QT interval, and seizure or severe muscular injury. However, reports describing venlafaxine-induced rhabdomyolysis with neuropathy remain scarce. Accordingly, we report such a case involving a 49-year-old woman with bilateral sciatic neuropathy combined with rhabdomyolysis following venlafaxine overdose. PATIENT CONCERNS: The patient complained of severe pain and tenderness in both thighs, weakness in both ankle flexor and extensor muscles, and a tingling sensation in the toes of both feet. DIAGNOSES: Bilateral sciatic neuropathy combined with rhabdomyolysis following venlafaxine overdose. INTERVENTION: Needle electromyography revealed fibrillation potentials and positive sharp waves, with absent recruitment in all the major muscles innervating the sciatic nerve bilaterally. Pelvic magnetic resonance imaging was performed after electromyography and revealed multifocal enhancement of signal intensity, suggesting muscle necrosis in the gluteus and thigh muscles, and swelling of both sciatic nerves on short tau inversion recovery (STIR) imaging sequences. OUTCOMES: Two months later, the patient's ankle dorsiflexion strength, measured with manual muscle test, was grade 0/0, and ankle plantar flexion was grade 0/0. The patient reported little sensation at the lateral and posterior aspects of her lower leg, and dorsum and sole of the foot. A follow-up electromyography study revealed improvement in the long head of the right biceps femoris; polyphasic motor unit action potentials with diminished recruitment were observed, but otherwise unchanged. LESSONS: When encountering patients who have overdosed on venlafaxine, it is very important to detect and treat severe complications such as cardiac toxicity, seizure, and rhabdomyolysis, among others. However, if rhabdomyolysis has already materialized, it should not be forgotten that the secondary damage caused by it. Physicians should rapidly detect and be minimized to mitigate future complications.

Memantine rescues prenatal citalopram exposure-induced striatal and social abnormalities in mice.

Prenatal exposure to citalopram (CTM), an antidepressant drug, has been associated with altered behavior, including autism-like symptoms in both human and rodent offspring. However, the neurological basis underlying these abnormal behaviors is not well understood. Here, we examined behavioral, morphological, and biochemical alterations in the male and female offspring of C57BL/6 mouse mothers that had been exposed to CTM during the last trimester of gestation. We observed abnormal behavior such as anxiety, altered locomotion and disordered social interactions in 2-5 months old offspring with prenatal CTM exposure. Using Golgi-Cox staining, we found that CTM caused significantly reduced dendritic length and number of dendritic branches in striatal neurons, as well as altered subunit levels of N-methyl-d-aspartate receptors (NMDARs) and calcium/calmodulin-dependent protein kinase II (CaMKII). Memantine, a selective NMDAR antagonist, improved prenatal CTM-induced abnormal protein levels and social interaction deficits. These results highlight potential mechanisms underlying the abnormal behavior observed in children who are prenatally exposed to CTM.

Toxicological Assessment of Venlafaxine: Acute and Subchronic Toxicity Study in Rats.

Antidepressants are the most commonly prescribed drugs for psychiatric treatment, and venlafaxine (VEN) is one of the most popular options. Venlafaxine is a nontricyclic dual-acting serotonin-norepinephrine reuptake inhibitor. Although an increased incidence of acute toxicity and addiction has been reported, controlled studies examining its toxic effects on different organs are still lacking. This study investigated the possible toxic effects of VEN on the liver, kidney, and gastric tissues. Three groups of rats were administered saline, a single LD50 dose (350 mg/kg), or 100 mg/kg VEN daily, followed by increases in the dose of 50 mg/kg every 10 days for 30 days (about 10 times the therapeutic doses). The following parameters of liver and kidney injury were then assayed: alanine aminotransferase, aspartate aminotransferase, γ-glutamyl transferase, prothrombin time, partial thromboplastin time, blood urea nitrogen, and serum creatinine. A histopathological examination was then conducted. Both acute and subchronic administration of VEN produced multiple clinical manifestations in the experimental animals, including seizures, coma, and even death. Moreover, the liver and renal function tests indicated injury in these tissues. Furthermore, the histopathological examination showed signs of organ toxicity after both acute and chronic VEN exposure. This study has shown that VEN has harmful effects on the liver, kidney, and stomach in either a single high dose (LD50) or repeated exposure to 10 times the therapeutic doses. As a result, strategies to increase awareness of these effects among physicians and the public are needed because this drug may be addictive.

Effects of acute and chronic exposures of fluoxetine on the Chinese fish, topmouth gudgeon Pseudorasbora parva.

Fluoxetine is a selective serotonin reuptake inhibitor used as an antidepressant and has been frequently detected in aquatic environments. However, its effects in fish from Asia remain relatively less studied. In this study, the topmouth gudgeon Pseudorasbora parva was exposed to 0, 50, and 200 µg/L of fluoxetine for 4 h and 42 d. The effects of fluoxetine on biometrics were compared to biochemical endpoints indicative of stress in different fish tissues (brain, liver, gills and intestine) following exposures. In fish exposed for 42 d, lipid peroxidation endpoints were enhanced 80% in the liver and gills. Acetylcholinesterase (AChE) activity was increased 40% after exposure to 50 µg/L and 55% at 200 µg/L following 4 h exposure. In contrast AChE was increased 26% (at 50 µg/L) after 42 d of exposures. Enhanced ethoxyresorufin-O-deethylase activity (EROD) was detected only in fish exposed to 50 µg/L of fluoxetine for 4 h. The activity of α-glucosidase (α-Glu) was also induced (at 200 µg/L) after 4 h of exposure. After 4 h of exposure, the activities of proteases in the intestine were generally inhibited at 200 µg/L. Both 4 h and 42 d exposures resulted in an increased hepatosomatic index (HSI) but did not affect the condition factor (CF). Our results demonstrate that fluoxetine significantly altered biochemical endpoints in P. parva after acute exposure and the morphological changes in liver size were not observed until 42 d of exposure.