Antidepressant Mixtures Research Articles

Differences in the response of Chlorella pyrenoidosa to three antidepressants and their mixtures in different light-dark start cycles.

The use of antidepressants is increasing along with the continuing spike in the prevalence of depression worldwide. As a result, more and more antidepressants are entering the water and probably does harm to the aquatic organisms and even human health. Therefore, three antidepressants, including fluoxetine (FLU), citalopram (CIT), and aspirin (APC), were selected to investigate the toxic risks of antidepressants and their mixtures to a freshwater green alga Chlorella pyrenoidosa (C. pyrenoidosa). Due light is critical for the growth of green algae, six different light-dark cycle experiments were constructed to investigate the differences in toxicity and interaction responses of C. pyrenoidosa to antidepressants and their ternary mixture designed by the uniform design ray method. The toxic effects of individual antidepressants and their mixtures on C. pyrenoidosa were systematically investigated by the time-dependent microplate toxicity analysis (t-MTA) method. Toxicity interactions (synergism or antagonism) within mixtures were analyzed by the concentration addition (CA) and the deviation from the CA model (dCA) models. The results showed that the toxicities of the three antidepressants were different, and the order was FLU > APC > CIT. Light-dark cycles obviously affect the toxicity of three antidepressants and their combined toxicity interaction. Toxicity of the three antidepressants increases with the duration of light but decreases with the duration of darkness. The ternary antidepressant mixture exhibits antagonism, and the longer the initial lighting is, the stronger the antagonism. The antagonism of the ternary mixture is also affected by exposure time and mixture components' pi as well as exposure concentration.

Presence and ecotoxicity of residual antidepressants in environmental samples

The consumption of antidepressants by the world population, especially during the pandemic of COVID-19, has increased. The increase in the use of these substances is intrinsically linked to their environmental detection. In this regard, the present work aims to evaluate the presence of the antidepressants venlafaxine, citalopram, fluoxetine, and sertraline in the Piracicaba River and to perform acute and chronic toxicity tests in Daphnia magna with the environmental concentration detected. The samples were extracted by solid phase extraction (SPE) methodology and analyzed by high-performance liquid chromatography coupled to a mass spectrometer with an electrospray ionization source. The highest environmental concentration detected for the acute and chronic tests with the individual antidepressants and their mixtures was used. The parameters used in the acute test were immobility and mortality, while in the chronic test were reproduction, survival, and dorsal and ventral size of D. magna. The acute risk quotient (RQ) was also estimated for each substance. The detection method was precise. The concentrations were determined to range from 1.0 to 4.48 ng L−1. The determined environmental concentrations do not present an acute risk for D. magna. According to the calculated RQ, antidepressants do not pose an acute risk to D. magna. The mixture of antidepressants using ambient concentrations did not cause dead or immobilized organisms. Reproduction and dorsal size of D. magna were affected by individual antidepressants and their mixtures. Antidepressants are present in the freshwater environment and can cause changes in non-target organisms; more studies are needed to verify the real impact of these substances on the entire trophic chain.

Assessing the effects of environmentally relevant concentrations of antidepressant mixtures to fathead minnows exposed over a full life cycle

Antidepressant drugs have been detected in municipal wastewater effluents (MWWEs) at ng/L to low μg/L concentrations. We exposed fathead minnow (Pimephales promelas) over a full lifecycle to a mixture of five antidepressants at concentrations similar to a MWWE (1× AntiD Mix); venlafaxine at 2400 ng/L, citalopram at 240 ng/L, fluoxetine at 90 ng/L, sertraline at 20 ng/L, and bupropion at 90 ng/L, and 10× these concentrations (i.e. 10× AntiD Mix). Mean measured concentrations of venlafaxine, citalopram, fluoxetine, sertraline, and bupropion were 2300, 160, 110, 7 ng/L, and below detection limits, respectively, for the 1× AntiD Mix, and 33,000, 2900, 1000, 210, and 100 ng/L, respectively for the 10× AntiD Mix. During the life-cycle exposure, no significant changes were observed in survival of fathead minnows. When male fish from the exposed treatments reached maturity, their weights were increased compared to control males. There were no significant differences in condition factor, gonadosomatic index, or liver-somatic index in the exposed fish. Exposed fathead minnows produced similar numbers of eggs as control fish, and there were no changes in nest-defense behaviours of male minnows. Egg quality, % fertilization, and % hatching in F1 fry were unaffected by exposure to the antidepressants. Eggs hatched 0.5 d earlier, deformities in fry were 50% lower, and there were transient decreases in length of F1 larvae at 8 days post-hatch in offspring from the treatment with the 10× AntiD Mix. Overall, exposure to the antidepressant mixture at environmentally relevant concentrations (i.e. 1× AntiD Mix) caused no adverse effects in fathead minnows. Exposure to the 10× AntiD Mix increased the weight of adult male minnows and caused subtle effects in F1 offspring. This study is the first to assess sublethal effects in fish exposed to mixtures of antidepressants over a full lifecycle. CapsuleNo effects were observed in fathead minnow exposed for a lifecycle to antidepressant mixtures at environmentally-relevant concentrations.

Joint effects of nine antidepressants on Raphidocelis subcapitata and Skeletonema marinoi: A matter of amine functional groups

Antidepressants are among the most prescribed pharmaceuticals throughout the world. Their presence has already been detected in several aquatic ecosystems worldwide and their effects on non-target organisms justify the growing concern of both the public and regulatory authorities. These emerging pollutants do not occur as isolated compounds but rather as multi-component mixtures, which may lead to increased adverse effects compared to individual compounds. Freshwater and marine algae seem particularly sensitive to pharmaceuticals, including antidepressants. Studies assessing the toxicity of antidepressant mixture to algae focused mainly on binary mixtures of selective serotonin reuptake inhibitors. In the present experiment, the freshwater algae Raphidocelis subcapitata (formerly known as Pseudokirchneriella subcapitata) and the marine diatom Skeletonema marinoi were exposed to equitoxic mixtures of 9 antidepressants (fluvoxamine, fluoxetine, sertraline, duloxetine, venlafaxine, clomipramine, amitriptyline, and citalopram) at different concentrations. The growth inhibition was measured. Results showed that the toxicity of this mixture was higher than the effects of each individual component, highlighting simple additivity or synergistic effects, whereas tested concentrations were below the 10% inhibition concentration (IC10) of each compound. Moreover, the QSAR analysis highlighted that antidepressants would act through narcosis (non-specific mode of action) towards the two species of algae. However, more specific effects can be observed by differentiating compounds with a primary/secondary amine from those with a tertiary amine. These mixture effects on algal species have to be assessed, especially since any impacts on phytoplankton could ultimately impact higher trophic levels (less food, secondary poisoning).

Suppressive immunoregulatory effects of three antidepressants via inhibition of the nuclear factor-κB activation assessed using primary macrophages of carp (Cyprinus carpio)

Antidepressants, having been applied for the treatment of major depressive disorder and other conditions for decades, are among the most commonly detected human pharmaceuticals in the aquatic environment. This study evaluated the immunotoxicity of acute exposure to environmentally relevant concentrations of amitriptyline, fluoxetine and mianserin using an in vitro primary macrophage model isolated from red common carp (Cyprinus carpio), and also explored their potential mechanisms of action. A potential suppressive immunoregulatory effect of antidepressant exposure was suggested based on the observed suppressive effects on oxidative stress parameters, bactericidal activity, NO production, and NO synthase activity, as well as pro-inflammatory cytokine gene expression, and a significant stimulatory effect on anti-inflammatory interleukin-10 and interferon cytokine gene expression and ATPase activities in macrophages after 6h-exposure to three individual antidepressants and a combination thereof. Notably, we also found these effects were significantly associated with a corresponding decrease in nuclear factor-κB (NF-κB) activity after antidepressants exposure, and the NF-κB antagonist significantly restrained the effects of antidepressants on gene expression of cytokines, indicating that antidepressants could alter the response of various immune-associated components via the inhibition of NF-κB. Moreover, time-dependent lethal concentrations of three antidepressants on primary macrophages were firstly determined at mg/L levels, and the synergetic effects of antidepressant mixtures were suggested and in particular, for some parameters including total antioxidant capacity and cytokine genes expression, they could be significantly affected by antidepressants exposure at concentrations as low as 10ng/L, which together thereby revealed the potential risk of antidepressants to aquatic life.

Simultaneous Spectrophotometric Determination of Imipramine Hydrochloride with Chlordiazepoxide and Nortriptyline Hydrochloride with Fluphenazine Hydrochloride

ABSTRACTSpectrophotometry was used with multivariate calibration to simultaneously determine compounds in mixtures. Two antidepressant mixtures were investigated: imipramine hydrochloride and chlordiazepoxide and nortriptyline hydrochloride and fluphenazine hydrochloride. Considerable spectral overlap and large differences in component concentrations were challenges. Since this type of analysis is often performed using complex algorithms, a simple strategy was used here for the simultaneous determination of both mixture components by classical least squares, principal component regression, and partial least squares. Experimental design was used to select the optimum parameters including the wavelength range, sampling interval, software, and derivative order. Accuracy was enhanced by proper wavelength selection. In addition, derivatives of the raw spectra improved the selectivity. The standard deviation, deviation of mean recovery from 100%, and prediction ability of the models were used as the responses. In respect to these terms, first-order derivatization of the spectra and a sampling interval of 1 nm provided the best results. In particular, the low concentration compounds in the mixtures (chlordiazepoxide and fluphenazine) were determined more accurately with precision lower than 3%. The strategy was used for the quality control of pharmaceuticals containing the mixtures without chemical pretreatment.

Effects of an antidepressant mixture on the brain serotonin and predation behavior of hybrid striped bass.

Antidepressants have been found in measurable concentrations in final treated wastewater effluent and receiving waters throughout the world. Studies have shown that these concentrations are typically not overtly toxic, but the psychotropic mode of action of these chemicals warrants examination of their behavioral effects. Exposure of hybrid striped bass to the antidepressants fluoxetine or venlafaxine alone has been shown to cause decreased brain serotonin levels and increased time to capture prey at concentrations typically 1 to 2 orders of magnitude higher than environmentally relevant concentrations. In the present study, equally effective doses of fluoxetine and venlafaxine were used to perform a mixture study, using a toxic unit approach to determine whether these antidepressants may act in an additive manner at lower concentrations. The results indicated that mixtures of these antidepressants caused decreased brain serotonin and increased time to capture prey at concentrations lower than reported in previous studies. Low concentration mixtures caused an additive effect on brain serotonin levels and time to capture prey, whereas higher concentrations were less than additive. The results were consistent with the dose addition concept, with higher concentration mixtures potentially saturating the effects on serotonin in the brain. Results from the present study indicate that antidepressants have the potential to be additive on the biochemical and individual scale, which necessitates more robust analysis of antidepressant mixtures and their potential to act together in low concentration scenarios.

Complex mixtures, complex responses: Assessing pharmaceutical mixtures using field and laboratory approaches.

Pharmaceuticals are present in low concentrations (<100 ng/L) in most municipal wastewater effluents but may be elevated locally because of factors such as input from pharmaceutical formulation facilities. Using existing concentration data, the authors assessed pharmaceuticals in laboratory exposures of fathead minnows (Pimephales promelas) and added environmental complexity through effluent exposures. In the laboratory, larval and mature minnows were exposed to a simple opioid mixture (hydrocodone, methadone, and oxycodone), an opioid agonist (tramadol), a muscle relaxant (methocarbamol), a simple antidepressant mixture (fluoxetine, paroxetine, venlafaxine), a sleep aid (temazepam), or a complex mixture of all compounds. Larval minnow response to effluent exposure was not consistent. The 2010 exposures resulted in shorter exposed minnow larvae, whereas the larvae exposed in 2012 exhibited altered escape behavior. Mature minnows exhibited altered hepatosomatic indices, with the strongest effects in females and in mixture exposures. In addition, laboratory-exposed, mature male minnows exposed to all pharmaceuticals (except the selective serotonin reuptake inhibitor mixture) defended nest sites less rigorously than fish in the control group. Tramadol or antidepressant mixture exposure resulted in increased splenic T lymphocytes. Only male minnows exposed to whole effluent responded with increased plasma vitellogenin concentrations. Female minnows exposed to pharmaceuticals (except the opioid mixture) had larger livers, likely as a compensatory result of greater prominence of vacuoles in liver hepatocytes. The observed alteration of apical endpoints central to sustaining fish populations confirms that effluents containing waste streams from pharmaceutical formulation facilities can adversely impact fish populations but that the effects may not be temporally consistent. The present study highlights the importance of including diverse biological endpoints spanning levels of biological organization and life stages when assessing contaminant interactions.

OPTIMIZATION OF THIN LAYER CHROMATOGRAPHY METHODS FOR SEPARATION AND IDENTIFICATION OF ANTIDEPRESSANTS IN THEIR MIXTURE

By conducting the toxicological analysis it is meaningful to determine the analytical system that could identify simultaneously several medicinal preparations quickly and precisely. The purpose of this work was to create and validate the method of thin-layer chromatography that would be suitable to separate the components of antidepressant mixture (amitriptyline hydrochloride, paroxetine hydrochloride, sertraline hydrochloride, fluvoxamine maleate and buspirone hydrochloride) and to identify them. The system was validated with regard to the sensitivity, repetition of data, resistance and particularity. The solvent systems with potential of high separation of components in their mixture were created: acetonitrile, methanol, ammonia solution 25 percent (85:10:5); acetonitrile, methanol, ammonia solution 25 percent (75:20:5); dichlormethane, 1,4-dioxane, ammonia solution 25 percent (50:45:5); dichlormethane, 1,4-dioxane, ammonia solution 25 percent (42:55:3); trichlormethane, 1,4-dioxane, ammonia solution 25 percent (25:70:5); trichlormethane, 1,4-dioxane, ammonia solution 25 percent (60:36:4). One of the most suitable solvent systems for separation of the analyzed mixture (sertraline, amitriptyline, paroxetine, buspirone, fluvoxamine) was determined – acetonitrile, methanol, ammonia solution 25 percent (85:10:5). When this solvent system was used, the average Rf values of the analyzed compounds differed the most. Validation was conducted – the relative standard deviation (RSD, percent) of the average Rf value of the analyzed compounds varied from 0,6 to 1,8 percent and did not exceed the permissible error of 5 percent. The sensitivity of methodology was determined by assessing the intensity of the mixture’s spots on the chromatographic plate. The detection limit of buspirone was 0,0012 µg; sertraline – 0,0008 µg; amitriptyline – 0,0004 µg; fluvoxamine – 0,0004 µg; paroxetine – 0,0008 µg. The resistance of results to the changed conditions – it was determined that when the amounts of the solvents acetonitrile and methanol were increased or decreased to two milliliters, the average Rf values of the analyzed compounds did not change statistically significantly

Improved chromatographic response function in HILIC analysis: Application to mixture of antidepressants

This paper presents exploration of chromatographic behavior in HILIC system by experimental design and improved chromatographic response function denoted as NCRF*. As a model mixture six antidepressants were chosen: selegiline, mianserine, sertraline, moclobemide, fluoxetine and maprotiline. Due to complexity of retention mechanisms in HILIC system, detailed examination of experimental space assessing the influence of important factors (acetonitrile content in the mobile phase, buffer concentration and pH of the mobile phase) and their interactions was done by applying 33 experimental design. NCRF* is developed and designed to be the only output of the system which simultaneously measures the separation of all the examined substances, the chromatographic run duration and the quality of the obtained peaks shape. It allowed objective estimation of overall chromatogram quality and excluded the arbitrary judgment in ambiguous situations. The applied function highlighted the influence of investigated factors on entire mixture and enabled identification of experimental regions where the chromatographic behavior was satisfactory. Applied experimental design strategy combined with NCRF* proved to be valuable assistance in HILIC separation of complex mixtures.

Selective uptake and biological consequences of environmentally relevant antidepressant pharmaceutical exposures on male fathead minnows

Antidepressant pharmaceuticals have been reported in wastewater effluent at the nanogram to low microgram-per-liter range, and include bupropion (BUP), fluoxetine (FLX), sertraline (SER), and venlafaxine (VEN). To assess the effects of antidepressants on reproductive anatomy, physiology, and behavior, adult male fathead minnows ( Pimephales promelas) were exposed for 21 days either to a single concentration of the antidepressants FLX, SER, VEN, or BUP, or to an antidepressant mixture. The data demonstrated that exposure to VEN (305 ng/L and 1104 ng/L) and SER (5.2 ng/L) resulted in mortality. Anatomical alterations were noted within the testes of fish exposed to SER and FLX, both modulators of the neurotransmitter serotonin. Additionally, FLX at 28 ng/L induced vitellogenin in male fish—a common endpoint for estrogenic endocrine disruption. Significant alterations in male secondary sex characteristics were noted with single exposures. Effects of single compound exposures neither carried over, nor became additive in the antidepressant mixtures, and reproductive behavior was not affected. Analysis of brain tissues from the exposed fish suggested increased uptake of FLX, SER and BUP and minimal uptake of VEN when compared to exposure water concentrations. Furthermore, the only metabolite detected consistently in the brain tissues was norfluoxetine. Similar trends of uptake by brain tissue were observed when fish were exposed to antidepressant mixtures. The present study demonstrates that anatomy and physiology, but not reproductive behavior, can be disrupted by exposure to environmental concentrations of some antidepressants. The observation that antidepressant uptake into fish tissues is selective may have consequences on assessing the mode-of-action and effects of these compounds in future studies.

Synthesis and characterization of long chain alkyl stationary phases on a silica hydride surface

C22 and C30 alkyl chains were attached to a silica hydride surface by a hydrosolation reaction. In each case both moieties were successfully bonded by either metal complex catalysis or free radical initiation. Carbon analysis, DRIFT spectra and13C CP-MAS NMR spectra confirm the bonding of the olefin to silica hydride. Conditions for maximum coverage were determined by a simplex procedure. Chromatographic evaluation of these long chain bonded phases was accomplished by separations of several types of mixtures: alkyl substituted benzenes; polycyclic aromatic hydrocarbons; carotenoids, tocopherols; tricyclic antidepressants; and peptides. The C30 column proved significantly better for separating the carotenoid and antidepressant mixtures and somewhat better for the peptide sample.

Derivative Spectrophotometric Determination of Some Tranquilizer - Antidepressant Mixtures

Abstract A method is presented for the determination of three tranquilizer-antipressant mixtures namely perphenazine amitriptyline, chlordiazepoxide-amitriptyline and trifluoperazine-isopropamide. The method depend on the application of first and second derivative spectrophotometric methods to resolve the interferance due to spectral overlapping. The method was applied to the determination of these compounds in synthecic mixtures and in pharmaceutical preparations. The coefficient of variation was less than 2%.