Mechanisms of hepatocellular toxicity associated with the components of St. John's Wort extract hypericin and hyperforin in HepG2 and HepaRG cells.

St. John's Wort preparations are used for the treatment of mild to moderate depression. They are usually well tolerated but can cause adverse reactions including liver toxicity in rare cases. To date, the mechanism(s) underlying the hepatotoxicity of St. John's Wort extracts are poorly investigated. We studied the hepatocellular toxicity of hypericin and hyperforin as the two main ingredients of St. John's Wort extracts in HepG2 and HepaRG cells and compared the effects to citalopram (a synthetic serotonin uptake inhibitor) with a special focus on mitochondrial toxicity and oxidative stress. In HepG2 cells, hypericin was membrane-toxic at 100 µM and depleted ATP at 20 µM. In HepaRG cells, ATP depletion started at 5 µM. In comparison, hyperforin and citalopram were not toxic up to 100 µM. In HepG2 cells, hypericin decreased maximal respiration starting at 2 µM and mitochondrial ATP formation starting at 10 µM but did not affect glycolytic ATP production. Hypericin inhibited the activity of complex I, II and IV of the electron transfer system and caused mitochondrial superoxide accumulation in cells. The protein expression of mitochondrial superoxide dismutase 2 (SOD2) and thioredoxin 2 (TRX2) and total and reduced glutathione decreased in cells exposed to hypericin. Finally, hypericin diminished the mitochondrial DNA copy number and caused cell necrosis but not apoptosis. In conclusion, hypericin, but not hyperforin or citalopram, is a mitochondrial toxicant at low micromolar concentrations. This mechanism may contribute to the hepatotoxicity occasionally observed in susceptible patients treated with St. John's Wort preparations.

Pharmacobezoar-Related Fatalities: A Case Report and a Review of the Literature.

ABSTRACT: Pharmacobezoars develop after an acute overdose or during routine drug administration. Here, the authors present a case of fatal multidrug overdose involving a 62-year-old woman. Her usual treatment included tramadol extended-release, citalopram, and mirtazapine. Furthermore, she self-medicated and misused her husband's medications. The autopsy revealed the presence of a voluminous medication bezoar in the stomach. No mechanical complication was noted. Toxicologic analyses were performed using gas chromatography with flame ionization detection, liquid chromatography with diode array detection, gas chromatography with mass spectrometry detection, and liquid chromatography coupled to tandem mass spectrometry. Tramadol (34,000 mcg/L), O-desmethyltramadol (2200 mcg/L), propranolol (6000 mcg/L), bromazepam (2500 mcg/L), zopiclone (1200 mcg/L), and citalopram (700 mcg/L) were identified in femoral blood at toxic concentrations. Interestingly, the femoral blood and vitreous humor concentration ratio was approximately 0.7. Furthermore, an English exhaustive literature search was performed using several different electronic databases without any limiting period to identify published pharmacobezoar-related fatalities. Seventeen publications were identified reporting a total of 19 cases. Decedents' mean age was 47.6 years [0.8-79] and a clear female predominance emerged. Several drugs were involved in pharmacobezoar formation. Death was attributed to drug toxicity in 13 cases, and to mechanical complications and/or sepsis in 4 cases. A mixed cause of death was reported in 2 cases. Although rare, pharmacobezoars remain potentially lethal and raise challenges in therapeutic management.

Investigating Population-Level Toxicity of the Antidepressant Citalopram in Harpacticoid Copepods Using In Vivo Methods and Bioenergetics-Based Population Modeling.

Recent research has revealed various lethal and sublethal effects of the selective serotonin reuptake inhibitor citalopram hydrobromide on the harpacticoid copepod Nitocra spinipes. In the present study, an individual-based model (IBM) grounded in the dynamic energy budget (DEB) theory was developed to extrapolate said effects to the population level. Using a generic DEB-IBM as a template, the model was designed to be as simple as possible, keeping model components that are outside the scope of the core DEB theory to a minimum. To test the model, a 56-day population experiment was performed at 0, 100, and 1000 µg citalopram hydrobromide L-1 . In the experiment, the populations quickly reached a plateau in the control and at 100 µg L-1 , which was correctly reproduced by the model and could be explained by food limitations hindering further population growth. At 1000 µg L-1 , a clear mismatch occurred: Whereas in the experiment the population size increased beyond the supposed (food competition-induced) capacity, the model predicted a suppression of the population size. It is assumed that the IBM still misses important components addressing population density-regulating processes. Particularly crowding effects may have played an important role in the population experiment and should be further investigated to improve the model. Overall, the current DEB IBM for N. spinipes should be seen as a promising starting point for bioenergetics-based copepod population modeling, which-with further improvements-may become a valuable individual-to-population extrapolation tool in the future. Environ Toxicol Chem 2023;42:1094-1108. © 2023 SETAC.

The protective role of melatonin in citalopram-induced reproductive toxicity via modulating nitro-oxidative stress and apoptosis in male mice.

Citalopram is the most potent selective serotonin reuptake inhibitor, commonly prescribed as an antidepressant, which can cause sexual dysfunction. Melatonin is a natural, highly effective antioxidant playing a pivotal role in the male reproductive system. The present study aimed to explore the ameliorating potential of melatonin on citalopram-evoked testicular toxicity and injury in mice. In this regard, mice were randomly divided into six groups: control, citalopram, melatonin 10 mg/kg, melatonin 20 mg/kg, melatonin 10 mg/kg plus citalopram, and melatonin 20 mg/kg plus citalopram. Adult male mice were intraperitoneally (i.p.) injected with 10 mg/kg of citalopram for 35 days with or without melatonin. At the end of the study, sperm parameters, testosterone level, testicular levels of malondialdehyde (MDA), nitric oxide (NO), total antioxidant capacity (TAC), and apoptosis (Tunel essay) were evaluated. Our findings revealed that melatonin restored spermatogenesis by improving sperm count, motility, viability, morphology, and chromatin integrity. Testosterone levels and the histopathology of the testes were markedly improved in the melatonin-administrated groups. Furthermore, citalopram administration significantly increased oxidative stress; however, melatonin restored antioxidant status by enhancing TAC levels and decreasing NO and MAD levels. More notably, citalopram therapy induced a significant increase in the number of Tunel-positive cells, while melatonin administration significantly mitigated the apoptotic impacts of citalopram. Together, melatonin therapy provides protection against citalopram-induced testicular damage via modulating nitro-oxidative stress and apoptosis, which provides evidence for melatonin as a promising treatment against antidepressant drug-associated reproductive toxicity and male sub/infertility.

Long-Term Exposure to SSRI Citalopram Induces Neurotoxic Effects in Zebrafish.

Residual antidepressants are of increasing concern worldwide, yet critical information on their long-term neurotoxic impacts on nontarget aquatic animals is lacking. Here, we investigated the long-term effects (from 0 to 150 days postfertilization) of the selective serotonin reuptake inhibitor citalopram (0.1-100 µg/L) on motor function, learning, and memory in zebrafish over two generations and explored the reversibility of the effect in F1 larvae. Unlike F0+ larvae, we found that F1+ larvae displayed decreased sensorimotor performance when continuously exposed to citalopram at 100 µg/L. No adverse effects were found in F1- larvae after they were transferred to a clean medium. Whole-mount immunofluorescence assays suggested that the motor impairments were related to axonal projections of the spinal motor neurons (MNs). For F0+ adults, long-term citalopram exposure mainly caused male-specific declines in motor, learning, and memory performance. Analysis of serotonergic and cholinergic MNs revealed no significant changes in the male zebrafish spinal cord. In contrast, the number of glutamatergic spinal MNs decreased, likely associated with the impairment of motor function. Additionally, treatment with 100 µg/L citalopram significantly reduced the number of dopaminergic neurons, but no significant neuronal apoptosis was observed in the adult telencephalon. Overall, this study provides neurobehavioral evidence and novel insights into the neurotoxic mechanisms of long-term citalopram exposure and may facilitate the assessment of the environmental and health risks posed by citalopram-containing antidepressant drugs.

Early Developmental Exposure to Fluoxetine and Citalopram Results in Different Neurodevelopmental Outcomes.

Although selective serotonin reuptake inhibitors are commonly prescribed for prenatal depression, there exists controversy over adverse effects of SSRI use on fetal development. Few studies have adequately isolated outcomes due to SSRI exposure and those due to maternal psychiatric conditions. Here, we directly investigated outcomes of exposure to widely-used SSRIs Fluoxetine and Citalopram on the developing nervous system of Xenopus laevis tadpoles, using an integrative experimental approach. We exposed tadpoles to low doses of Citalopram and Fluoxetine during a critical developmental period and found that different experimental groups displayed opposing behavioral effects. While both groups showed reduced schooling behavior, the Fluoxetine group showed increased seizure susceptibility and reduced startle habituation. In contrast, Citalopram treated tadpoles had decreased seizure susceptibility and increased habituation. Both groups had abnormal dendritic morphology in the optic tectum, a brain area important for behaviors tested. Whole-cell electrophysiological recordings of tectal neurons showed no differences in synaptic function; however, tectal cells from Fluoxetine-treated tadpoles had decreased voltage gated K+ currents while cells in the Citalopram group had increased K+ currents. Both behavioral and electrophysiological findings indicate that cells and circuits in the Fluoxetine treated optic tecta are hyperexcitable, while the Citalopram group exhibits decreased excitability. Taken together, these results show that early developmental exposure to SSRIs is sufficient to induce neurodevelopmental effects, however these effects can be complex and vary depending on the SSRI. This may explain some discrepancies across human studies, and further underscores the importance of serotonergic signaling for the developing nervous system.

Making Sense of Life-History Effects of the Antidepressant Citalopram in the Copepod Nitocra spinipes Using a Bioenergetics Model.

The global consumption of human antidepressants has steadily increased over the last years. The most widely prescribed antidepressants are the selective serotonin reuptake inhibitors (SSRIs), which have been linked to various life-history effects in nontarget organisms. We investigated the effects of the SSRI citalopram hydrobromide on the life history of the copepod Nitocra spinipes. Slight but significant developmental delay effects were observed at nominal concentrations of 0.1 and 1 µg/L, with stronger effects occurring at measured concentrations of 178 µg/L and above. At 77 µg/L and above, a significant increase in adult body length and offspring production/brood was found, although the time between brood releases remained unaffected. The pre-adult surviving fraction was significantly reduced (by 44%) at 765 µg/L. For a mechanistic evaluation of these observations, we used a bioenergetics model for N. spinipes based on the dynamic energy budget theory. Toxicokinetic and toxicodynamic submodels were used to dynamically simulate the chemical uptake and elimination, as well as dose-response relationships for hypothetical physiological modes of action and survival over time. Although none of the commonly invoked physiological modes of action, acting on assimilation, maintenance, growth, or offspring production, could explain the observed combination of effects, a newly proposed physiological mode of action acting on the process of maturation delivered correct predictions in terms of each effect's direction. The model fits could be further improved by allowing for a gentler concentration-effect slope and by adding an auxiliary physiological mode of action acting on the reproduction efficiency. The quantitative explanations provided in the present study offer a starting point for exploratory simulation studies investigating the effects of SSRIs at higher ecological levels. Environ Toxicol Chem 2021;40:1928-1939. © 2021 SETAC.

Divergent Response to the SSRI Citalopram in Male and Female Three-Spine Sticklebacks (Gasterosteus aculeatus).

Selective serotonin reuptake inhibitors (SSRIs) are psychotropic pharmaceuticals used as antidepressants. SSRIs are commonly found in surface waters in populated areas across the globe. They exert their effect by blocking the serotonin re-uptake transporter in the presynaptic nerve ending. The present study examined whether behavioural effects to exposure to SSRI citalopram depend on personality and sex in the stickleback (Gasterosteus aculeatus). Three aspects of stickleback behaviour are examined: feeding behaviour, aggression, and boldness. We exposed sticklebacks to 350-380 ng/l citalopram for 3 weeks. Feeding and aggressive behaviour were recorded before and after exposure, whereas scototaxis behaviour was tested after exposure. The results show treatment effects in feeding and aggressive behaviour. Feeding is suppressed only in the male group (χ2 = 20.4, P < 0.001) but not in the females (χ2 = 0.91, P = 0.339). Aggressive behaviour was significantly affected by treatment (χ2 = 161.9, P < 0.001), sex (χ2 = 86.3, P < 0.001), and baseline value (χ2 = 58.8, P < 0.001). Aggressiveness was suppressed by citalopram treatment. In addition, the fish showed no change in aggression and feeding behaviour over time regardless of sex and treatment, which indicate personality traits. Only females are affected by treatment in the scototaxis test. The exposed females spent significantly (χ2 = 5.02, P = 0.050) less time in the white zone than the female controls.

Toxicity Profile, Pharmacokinetic, and Drug-Drug Interaction Study of Citalopram and Sertraline Following Oral Delivery in Rat: An LC-MS/MS Method for the Simultaneous Determination in Plasma.

The burden of depression and other mental disorders is on the rise globally, and successful treatment sometimes requires modifications of drugs and/or dose regimens. The development of novel analytical methods for the determination of antidepressant drugs in biological fluids is thus urgently required. Herein, a sensitive, robust, and rapid liquid chromatographic coupled tandem mass spectrometric method was developed and validated for the determination of citalopram (CIT) and sertraline (SER) in rat plasma after oral administration. The analytes of interest and internal standard (duloxetine (DUL)) were extracted from 100 µL of plasma with solid-phase extraction on an Oasis HLB cartridge followed by the separation with gradient elution with water containing 0.1% formic acid and acetonitrile on an Agilent Eclipse Plus ODS (4.6 × 100 mm, 3.5 µm) column at flow rate 0.2 mL min-1. The triple quadrupole mass spectrometry was applied via electrospray ionization source for detection. The fragmentation pattern of the protonated CIT, SER, and DUL was elucidated using multiple reaction monitoring of the transitions of m/z 325.2 to 109, 306.1 to 158.9, and 298.1 to 154.1 as [M + H]+ for CIT, SER, and DUL, respectively. The proposed method has been validated as per US-FDA bioanalytical guidelines in terms of linearity, accuracy, precision, matrix effects, stability, selectivity, and recovery. The method was linear over the concentration range of 1-2000 and 1-1000 ng mL-1 with the lower limit of detection of 0.12 and 0.19 ng mL-1 for CIT and SER, respectively. The interday and intraday precisions and accuracy expressed by the relative standard deviation and the relative standard error were both lower than 11.1% and 2.1%, respectively. The proposed method was successfully applied for the pharmacokinetics and drug monitoring studies of CIT and SER in rat plasma after a single oral dose of 120 mg kg-1 of CIT and SER. Coadministration of SER with CIT has affected the peak plasma concentrations, maximum plasma concentration time, area under the concentration-time curve, and oral clearance of CIT. Molecular modeling study showed that SER could competitively inhibit CYP2D6, the main enzyme involved in CIT metabolism. A possible drug-drug interaction in psychiatric patients undergoing chronic SER and CIT treatment is therefore worthy of more attention in an effort to avoid side effects and serotonin syndrome.

Do environmentally relevant concentrations of fluoxetine and citalopram impair stress-related behavior in zebrafish (Danio rerio) embryos?

Selective serotonin reuptake inhibitors (SSRIs) have been shown to interfere with various physiological functions of aquatic organisms, yet the neuroactive potential of low concentrations of SSRIs in the aquatic environment is unclear. The current study investigated the effects of fluoxetine and citalopram on the visual motor response (VMR) of 107 h old zebrafish (Danio rerio) embryos. Results document a reduction in stress-related swimming activity of zebrafish embryos at environmentally relevant concentration levels, with fluoxetine being more effective than citalopram. Further experiments were designed to elucidate (1) if the lower neuroactive potential of citalopram is due to differences in uptake kinetics, (2) if the metabolite of fluoxetine, norfluoxetine, contributes to the neuroactive potential of fluoxetine, (3) and how SSRIs and their metabolites interact in equimolar mixtures. At the stage of 120 h, zebrafish embryos accumulate citalopram at significantly lower rates (up to 127 times) than fluoxetine. Moreover, it was demonstrated that norfluoxetine reduces the embryonic VMR similarly to fluoxetine resulting in additive effects of these substances on stress-related behavior in zebrafish embryos. In contrast, the interaction of fluoxetine, norfluoxetine and citalopram varied with test concentrations of the equimolar mixtures. Findings provide evidence that environmentally relevant concentrations of fluoxetine reduce stress-related behavior of zebrafish embryos, while these effects may be enhanced by the interaction of multiple SSRIs and their metabolites in environmental exposure scenarios.

Identification and characterization of citalopram new metabolites with the use of UHPLC-Q-TOF technique: In silico toxicity assessment of the identified transformation products.

In this study the metabolite profiling of citalopram with the use of human liver microsomes as well as the complementary photocatalytic method were established. This strategy allowed the detection of five metabolites of citalopram including 3-hydroxycitalopram and 3-oxocitalopram which were found as a new and not previously described metabolites of this drug The photocatalytic simulation of metabolism was carried out using tungsten (VI) oxide nanopowders with the different particle sizes, which allowed to examine the effect of this photocatalyst parameter on the mapping of metabolic processes. The accurate characterization of all observed structures was possible due to the use of ultra-high-pressure liquid chromatography and high-resolution mass spectrometry combined system as a highly useful technique in drug metabolism studies. In order to perform the toxicity prediction of citalopram and its metabolites, the acute toxicity to rodents, as well as genotoxicity, carcinogenicity, developmental toxicity and receptor-mediated toxicity was calculated basing on the in silico tools.

The role of chronic nutritional supplements consumption in a fulminant serotonin syndrome due to citalopram intoxication / El papel del consumo crónico de suplementos nutricionales en un síndrome serotoninérgico fulminante debido a intoxicación por citalopram

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Analysis of tail coiling activity of zebrafish (Danio rerio) embryos allows for the differentiation of neurotoxicants with different modes of action.

In (eco)toxicology, there is a critical need for efficient methods to evaluate the neurotoxic potential of environmental chemicals. Recent studies proposed analysis of early coiling activity in zebrafish embryos as a powerful tool for the identification of neurotoxic compounds. In order to demonstrate that the analysis of early tail movements of zebrafish embryos allows for the discrimination of neurotoxicants acting via different mechanisms, the present study investigated the effects of four different neurotoxicants on the embryogenesis (fish embryo toxicity test) and early tail coiling movements of zebrafish embryos. Cadmium predominantly increased the frequency of tail coiling at the late pharyngula stage. Dichlorvos delayed embryonic development and caused convulsive tail movements resulting in prolonged duration of tail coils. Embryos exposed to teratogenic concentrations of fluoxetine and citalopram displayed absence of spontaneous tail movements at 24 h post-fertilization. In contrast, a non-teratogenic test concentration of citalopram decreased coiling frequency at multiple time points. Results demonstrated that the analysis of tail coiling movements of zebrafish embryos has the potential to discriminate neurotoxic compounds with different primary modes of action. In addition, chemical-induced effects on coiling activity were shown to potentially overlap with effects on embryogenesis. Further studies are needed to clarify the interplay of unspecific developmental toxicity of neurotoxic chemicals and effects resulting from specific neurotoxic mechanisms.

The Psychoactive Drug Escitalopram Affects Foraging Behavior in Zebrafish (Danio rerio).

Selective serotonin reuptake inhibitors (SSRIs) are psychoactive pharmaceuticals that have been detected intact in natural waters globally. Laboratory experiments have reported that several SSRIs inhibit fish foraging behavior, but data for the SSRI escitalopram are lacking. The objectives of the present study were to determine whether escitalopram affects feeding behavior in zebrafish and whether possible sex differences exist. We exposed female and male zebrafish (Danio rerio) to 0.00, 0.10, and 1.50 µg/L of escitalopram in flow-through tanks for a 3-wk exposure period. We used a video tracking system with high temporal and spatial resolution to collect data on zebrafish swimming patterns in test tanks containing a food source. The results show a more pronounced effect of escitalopram in males compared with females. At the assumed most environmentally relevant concentration (0.10 µg/L), male average feeding time/visit and maximum feeding duration were significantly reduced by 27 and 42%, respectively. In addition, male total feeding duration was also significantly reduced (by 73%) at the highest concentration (1.50 µg/L). In females, only the maximum feeding duration was significantly reduced (by 41%) in the 0.10 µg/L treatment group. Hence, we reject our initial hypothesis that female feeding behavior is more vulnerable to escitalopram. There was no effect of escitalopram on length or weight among the experimental groups. The present study demonstrates that escitalopram, like other SSRIs, can inhibit fish foraging behavior and therefore potentially disturb natural food chains. Finally, our study suggests that SSRIs can both be sex and behavior specific. Environ Toxicol Chem 2019;38:1902-1910. © 2019 SETAC.

Study of DNA-Binding Activity and Antibacterial Effect of Escitalopram Oxalate, an Extensively Prescribed Antidepressant.

Escitalopram oxalate (EO) is considered as one of the extensively prescribed antidepressant drug in Turkey and some other countries, therefore this research was aimed to study the interaction of the drug with DNA and study of the substance effect on bacterial growth. The absorption value of the drug solution at 238 nm was increased when DNA was added gradually to it and it showed hyperchromism effect. The value obtained for DNA binding constant (Kb) was 0.035 M -1. When we added the CuCl2 2H2O to the mixture, any breakage was not shown in double strand DNA in comparison with control DNA. In addition low concentration of EO couldn't protect DNA (0.5273 µmole bp) against Hydroxyl free radical (0.12 µmole) although it could protect the DNA when it was at the same or higher concentrations (0.5273, 5.273 and 252.73 µmole) than the DNA concentration. In addition, MIC of the drug for E.coli and Bacillus subtilis was almost 0.185 mM and 0.55 mM respectively. The E.coli strain was killed at concentrations 45, 15, 5 mM while the Bacillus subtilis was stable against all of the concentrations.

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.

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.

Environmentally relevant concentrations of tramadol and citalopram alter behaviour of an aquatic invertebrate.

Environmental pollution by pharmaceutically active compounds, used in quantities similar to those of pesticides and other organic micropollutants, is increasingly recognized as a major threat to the aquatic environment. These compounds are only partly removed from wastewaters and, despite their low concentrations, directly and indirectly affect behaviour of freshwater organisms in natural habitats. The aim of this study was to behaviourally assess the effects of an opioid painkiller (tramadol) and antidepressant drug (citalopram) on behaviour patterns of a clonal model species, marbled crayfish. Animals exposed to environmentally relevant concentrations of both tested compounds (∼1 µg l-1) exhibited significantly lower velocity and shorter distance moved than controls. Crayfish exposed to tramadol spent more time in shelters. Results were obtained by a simple and rapid method recommended as suitable for assessment of behaviour in aquatic organisms exposed to single pollutants and combinations.

In vitro genotoxic and cytotoxic effects of doxepin and escitalopram on human peripheral lymphocytes.

Antidepressants are drugs used for the treatment of many psychiatric conditions including depression. There are findings suggesting that these drugs might have genotoxic, carcinogenic, and/or mutagenic effects. Therefore, the present in vitro study is intended to investigate potential genotoxic and cytotoxic effects of the antidepressants escitalopram (selective serotonin reuptake inhibitor) and doxepin (Tricyclic antidepressant) on human peripheral lymphocytes cytokinesis-block micronucleus (CBMN), sister chromatid exchange (SCE), and single cell gel electrophoresis (alkaline comet assay) were used for the purpose of the study. In the study, four different concentrations of both drugs (1, 2.5, 5, and 10 µg/mL) were administered to human peripheral lymphocytes for 24 h. The tested concentrations of both drugs were found to exhibit no cytotoxic and mitotic inhibitory effects. SCE increase caused by 5 and 10 µg/mL of escitalopram was found statistically significant, while no statistically significant increase was observed in DNA damage and micronucleus (MN) formation. Moreover, the increase caused by doxepin in MN formation was not found statistically significant. Besides, 10 µg/mL of doxepin was demonstrated to significantly increase arbitrary unit and SCE formation. These findings suggest that the investigated concentrations of escitalopram and doxepin were non-cytotoxic but potentially genotoxic at higher concentrations.

Developmental exposure to the SSRI citalopram causes long-lasting behavioural effects in the three-spined stickleback (Gasterosteus aculeatus).

Selective Serotonin re-uptake inhibitors (SSRIs) are a class of psychotropic drugs used to treat depression in both adolescents and pregnant or breast-feeding mothers as well as in the general population. Recent research on rodents points to long-lasting behavioural effects of pre- and perinatal exposure to SSRIs which last into adulthood. In fish however, studies on effects of developmental exposure to SSRIs appears to be non-existent. In order to study effects of developmental SSRI exposure in fish, three-spine sticklebacks were exposed to 1.5 µg/l of the SSRI citalopram in the ambient water for 30 days, starting two days post-fertilisation. After approximately 100 days of remediation in clean water the fish were put through an extensive battery of behavioural tests. Feeding behaviour was tested as the number of bites against a piece of food and found to be increased in the exposed fish. Aggression levels were measured as the number of bites against a mirror image during 10 min and was also found to be significantly increased in the exposed fish. Novel tank behaviour and locomotor activity was tested in an aquarium that had a horizontal line drawn half-way between the bottom and the surface. Neither the latency to the first transition to the upper half, nor the number of transitions or the total time spent in the upper half was affected by treatment. Locomotor activity was significantly reduced in the exposed fish. The light/dark preference was tested in an aquarium where the bottom and walls were black on one side and white on the other. The number of transitions to the white side was significantly reduced in the exposed fish but there was no effect on the latency to the first transition or the total time spent in the white half. The results in the current study indicate that developmental SSRI exposure causes long-lasting behavioural effects in fish and contribute to the existing knowledge about SSRIs as environmental pollutants.