Antidepressant Pharmaceuticals Research Articles

A comprehensive insight into the transformation pathways and products of fluoxetine and venlafaxine in wastewater based on molecular networking nontarget screening

Fluoxetine (FLX) and venlafaxine (VEN) are widely used antidepressant pharmaceuticals and were frequently detected in wastewater. Despite incomplete mineralization during biological wastewater treatment processes has been revealed, little is known about their transformation products (TPs) formed in the biological systems. To fill this gap, batch reactors and molecular networking nontarget screening were employed to identify the TPs and explore the transformation pathways of FLX and VEN in wastewater. On the basis, the concentrations of the TPs in wastewater treatment plants (WWTPs) were determined and their toxicity was predicted. The removal rate constants per unit of biomass of FLX and VEN were up to 0.3192 and 0.1644 L/(gMLSS*d) in batch experiments, respectively. Subsequently, 11 TPs of VEN and 11 TPs of FLX were tentatively identified, among which 9 TPs of FLX and 5 TPs of VEN were newly reported in this study. The proposed transformation pathways provided new insights into the transformation reactions including dehydrogenation, N-formylation and hydroxylation for FLX, and formylation, epoxidation and methylation for VEN. Particularly, N-succinylation and demethylation were the dominant transformation pathways for FLX and VEN during transformation processes. The results of sampling campaigns revealed that the accumulated concentration of TPs were higher than the concentrations of VEN in effluent of WWTPs. In silico prediction results suggested that certain TPs have higher toxicity, persistence and biodegradability than their corresponding parent compounds of FLX and VEN. In addition, VEN-TP264(a) showed higher ecological risks than VEN. This study revealed the transformation processes and fate of FLX and VEN in wastewater, indicating that greater concerns should be exerted on the toxicity detection and control of the TPs of FLX and VEN in the treated wastewater.

Effect of common low-molecular-weight organic acid on the photodegradation of sertraline by ferrihydrite

Sertraline is one of the most commonly used antidepressant pharmaceuticals with ubiquitous distribution in the aqueous environment. However, the environmental behavior of sertraline in the co-presence of low-molecular-weight organic acid (LMWOA) and iron oxide mineral is still poorly understood. In this study, the photodegradation of sertraline was systematically investigated in a common photosensitizing system (ferrihydrite (Fh)-LMWOA). Six LMWOAs, including citrate acid (CA), tartrate acid (TA), malate acid (MA), lactate acid (LA), succinate acid (SA) and malonic acid (MOA) were chosen as the representatives. Our results implied that the different Fe3+ dissolution rates would lead to rather different sertraline degradation patterns following the order of Fh-CA > Fh-TA > Fh-MA > Fh-LA > Fh-SA > Fh-MOA. The reaction was initiated by the interaction between LMWOA and Fh via ligand-promoted-dissolution mechanism. Furthermore, the Fe3+ dissolution rates also showed a strong correlation with the metal-organic complexation constants, indicating that the photodegradation process is strongly related to the complexation ability of LMWOA with Fe3+. •OH, O2•- and CO2•- were detected, indicating that they contributed to the photodegradation of sertraline. •OH was demonstrated to be the dominant Reactive oxygen species (ROS) for the degradation of sertraline, and the detailed transformation pathways were proposed based on the product analysis and theoretical calculation. According to the ecological structure activity relationship estimation, the photodegradation products of sertraline possessed lower toxicity compared to the parent compound. These findings contribute to a more comprehensive understanding of the environmental fate of sertraline and evaluate its potential ecotoxicity in natural systems.

Degradation of antidepressant pharmaceuticals by photoperoxidation in diverse water matrices: a highlight in the evaluation of acute and chronic toxicity.

Photoperoxidation (UV/H2O2) was used to degrade three of the worldwide most consumed antidepressant pharmaceuticals-bupropion, escitalopram, and fluoxetine-in ultrapure water, drinking tap water, surface water, and reclaimed water. The study was performed with antidepressants in concentration levels in which these compounds usually occur in the water matrices. Online solid-phase extraction coupled to UHPLC-MS/MS was used to quantify the analytes during degradation studies. The UV/H2O2 process was able to degrade bupropion and fluoxetine in ultrapure water, using 0.042mmolL-1 of H2O2 and 1.9kJ of UV-C irradiation. Nevertheless, escitalopram, which had the most recalcitrant character among the studied antidepressants, needed a tenfold more oxidant and UV-C irradiation. The primary metabolites of the antidepressants were identified asthe major by-products generated by the UV/H2O2 process, and they persisted in the solution even when the parent compound was degraded. The residual toxicity of the solution was evaluated for two different trophic levels. The UV/H2O2 process reduced the toxicity of the solution to Raphidocelis. subcapitata microalgaeafter 30min of reaction. On the other hand, the toxicity of the residual solution increased over the reaction time to the marine bacteria Vibrio fischeri (reaching up to 48.3% of bioluminescence inhibition after 60min of reaction). Thus, our results evidenced that the toxicity against different trophic levels and the monitoring of the by-products formed are important aspects to be considered regarding the safety of the treated solution and the optimization of the treatment process.

Molecular and behavioral responses of zebrafish embryos/larvae after sertraline exposure

Sertraline (SER) is one of the most frequently detected antidepressant drugs in aquatic environments. However, knowledge regarding SER-induced behavioral alterations in fish is insufficient, as well as the mechanisms underlying SER-induced toxicity. The present study aimed to determine behavioral and molecular responses in larval fish following SER exposure with a focus on its mode of action. Zebrafish embryos (~6 h-post-fertilization, hpf) were exposed to one of three concentrations of SER (1, 10, 100 μg/L) for 6 days, respectively. Evaluated parameters included development, behavior, transcripts related to serotonin signaling, serotonin levels, and acetylcholinesterase activity. Accelerated hatching of zebrafish embryos was observed for those fish exposed to 100 μg/L SER at 54 hpf. Locomotor activity (e.g. distance moved and mobile cumulative duration) was significantly reduced in larval zebrafish following exposure to 10 and 100 μg/L SER. Conversely, larval fish showed increased dark-avoidance after exposure to 1–100 μg/L SER. Of the measured transcripts related to serotonin signaling, only serotonin transporter (serta) and serotonin receptor 2c (5-ht2c) mRNA levels were increased in fish in response to 10 μg/L SER treatment. However, serotonin levels were unaltered in larvae exposed to SER. There were no differences among groups in acetylcholinesterase activity at any concentration tested. Taking together, the results evidenced that exposure to SER alters behavioral responses in early-staged zebrafish, which may be related to the abnormal expression of 5-ht2c. This study elucidates molecular responses to SER and characterizes targets that may be sensitive to antidepressant pharmaceuticals in larval fish.

New-generation bar adsorptive microextraction (BAμE) devices for a better eco-user-friendly analytical approach–Application for the determination of antidepressant pharmaceuticals in biological fluids

The present contribution aims to design new-generation bar adsorptive microextraction (BAμE) devices that promote an innovative and much better user-friendly analytical approach. The novel BAμE devices were lab-made prepared having smaller dimensions by using flexible nylon-based supports (7.5 × 1.0 mm) coated with convenient sorbents (≈ 0.5 mg). This novel advance allows effective microextraction and back-extraction (‘only single liquid desorption step’) stages as well as interfacing enhancement with the instrumental systems dedicated for routine analysis. To evaluate the achievements of these improvements, four antidepressant agents (bupropion, citalopram, amitriptyline and trazodone) were used as model compounds in aqueous media combined with liquid chromatography (LC) systems. By using an N-vinylpyrrolidone based-polymer phase good selectivity and efficiency were obtained. Assays performed on 25 mL spiked aqueous samples, yielded average recoveries in between 67.8 ± 12.4% (bupropion) and 88.3 ± 12.1% (citalopram), under optimized experimental conditions. The analytical performance also showed convenient precision (RSD < 12%) and detection limits (50 ng L−1), as well as linear dynamic ranges (160–2000 ng L−1) with suitable determination coefficients (r2 > 0.9820). The application of the proposed analytical approach on biological fluids showed negligible matrix effects by using the standard addition methodology. From the data obtained, the new-generation BAμE devices presented herein provide an innovative and robust analytical cycle, are simple to prepare, cost-effective, user-friendly and compatible with the current LC autosampler systems. Furthermore, the novel devices were designed to be disposable and used together with negligible amounts of organic solvents (100 μL) during back-extraction, in compliance with the green analytical chemistry principles. In short, the new-generation BAμE devices showed to be an eco-user-friendly approach for trace analysis of priority compounds in biological fluids and a versatile alternative over other well-stablished sorption-based microextraction techniques.

Occurrence of antidepressant residues in the sewage-impacted Vistula and Utrata rivers and in tap water in Warsaw (Poland)

Antidepressants, even at low concentrations, can reveal some adverse effects on aquatic life due to disturbing homeostasis throughout the central and peripheral nervous system both in vertebrates and invertebrates. To date there have not been any reports regarding the presence of these pharmaceuticals in surface and tap waters in Eastern Europe. Therefore the aim of this study was to determine the presence of 21 antidepressant pharmaceuticals at specific points of the main Polish river – the Vistula, a smaller river of the Warsaw region – the Utrata, as well as in tap water samples of Warsaw. Samples were collected twice at one month intervals and analysed using solid-phase extraction (SPE) technique coupled with the liquid chromatography–electrospray ionisation–tandem mass spectrometer (LC–MS/MS) method operated under the multiple reaction monitoring mode (MRM).This is the first study where active compounds such as moclobemid or trazodone in the environment have been investigated.Environmental risk assessment of antidepressants in Poland was estimated on the basis of annuals sale data extracted from the NFZ (Narodowy Fundusz Zdrowia—National Health Service) base of reimbursed pharmaceuticals1. Predicted environmental concentration (PEC) of target pharmaceuticals were compared with their measured concentration (MEC).Moreover, the application of the EMEA/CHMP guideline for environmental risk assessment of the antidepressants was discussed. The highest concentration of antidepressants was observed in the small river Utrata. In tap water only trace amounts of antidepressants including citalopram (up to 1.5ng/l), mianserin (up to 0.9ng/l), sertraline (<3.1ng/l), moclobemid (up to 0.3ng/l) and venlafaxine (up to 1.9ng/l) were detected. However this highlights their inadequate elimination in the drinking waste treatment facility. The presence of antidepressants in drinking water and the aquatic environment could have long-term effects even at low exposure level, especially since synergy amongst pharmaceutical pollutants may occur.

Quantitative Determination of Antidepressants and Their Select Degradates by Liquid Chromatography/Electrospray Ionization Tandem Mass Spectrometry in Biosolids Destined for Land Application

Antidepressants are one of the most widely dispensed classes of pharmaceuticals in the United States. As wastewater treatment plants are a primary source of pharmaceuticals in the environment, the use of biosolids as fertilizer is a potential route for antidepressants to enter the terrestrial environment. A microsolvent extraction method, utilizing green chemistry, was developed for extraction of the target antidepressants and degradation products from biosolids, or more specifically lagoon biosolids. Liquid chromatography/tandem mass spectrometry was used for quantitative determination of antidepressants in the lagoon biosolid extracts. Recoveries from matrix spiking experiments for the individual antidepressants had an average of 96%. The limits of detection for antidepressant pharmaceuticals and degradates ranged from 0.36 to 8.0 ng/kg wet weight. The method was applied to biosolids destined for land application. A suite of antidepressants was consistently detected in the lagoon biosolid samples, and thus antidepressants are being introduced to terrestrial environments through the land application of these biosolids. Sertraline and norsertraline were the most abundant antidepressant and degradation product detected in the biosolid samples. Detected, individual antidepressant concentrations ranged from 8.5 ng/kg (norfluoxetine) to 420 ng/kg wet weight (norsertraline).

Advanced oxidation treatment and photochemical fate of selected antidepressant pharmaceuticals in solutions of Suwannee River humic acid

Antidepressant pharmaceuticals have recently been detected at low concentrations in wastewater and surface water. This work reports studies of the direct and indirect photochemical fate and treatment by advanced oxidation of three antidepressant compounds (duloxetine, venlafaxine and bupropion) in solutions of humic acid in order to elucidate their behavior in the natural environment prior to reaching a water treatment facility and potentially entering a potable water supply. Humic acid solution was prepared by adding to distilled water a known amount of organic matter as a photosensitizer. All three antidepressants react very rapidly with hydroxyl radicals (OH) and hydrated electrons (e−aq) with rate constants of ∼108 to 1010M−1s−1, but significantly slower with singlet oxygen (1ΔO2) (∼103 to 105M−1s−1). The steady-state concentrations of OH and 1ΔO2, in a sample of humic acid solution were measured and used with the second order rate constants to show that the hydroxyl radical was an order of magnitude more effective than the singlet oxygen in the solar-induced photochemical degradation of the antidepressants. Excited state dissolved organic matter also accounted for a substantial portion of degradation of duloxetine, decreasing its half-life by 27% under solar irradiation. Several reaction pathways and by-products arising from the photodegradation were identified using gamma-irradiation followed by LC–MS analysis.

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.

Antidepressants: Current Strategies and Future Opportunities

Recent advances in research on depression have confirmed that it is common, recurrent and disabling mental disorder. Current medication for the treatment of depression have limited efficacy and delayed onset of therapeutic action. In view of the limitation of the current antidepressant pharmaceuticals, tremendous research efforts are ongoing to search for a pharmacological treatment which may improve antidepressive efficacy, onset of action or even both therapeutic parameters. To address these needs, numerous combination therapies that maintain the benefits associated with selective serotonin reuptake inhibitors (SSRIs) but attempts to improve efficacy or reduce side effects by additional mechanism (5-HT₁A, 5-HT₂C) and newer approaches targeting excitatory (glutamate, NMDA, mGluR₂, mGluR₅) or inhibitory aminoacid system (GABA) or peptidergic system(neurokinin1, corticotrophin releasing factor1, melanin concentrating hormone1) have been identified. The goal of this review is to give a brief overview of the major advances in monoamine based treatment strategies and the new emerging approaches in the treatment of depression.

Antidepressant Pharmaceuticals in Two U.S. Effluent-Impacted Streams: Occurrence and Fate in Water and Sediment, and Selective Uptake in Fish Neural Tissue

Antidepressant pharmaceuticals are widely prescribed in the United States; release of municipal wastewater effluent is a primary route introducing them to aquatic environments, where little is known about their distribution and fate. Water, bed sediment, and brain tissue from native white suckers (Catostomus commersoni) were collected upstream and at points progressively downstream from outfalls discharging to two effluent-impacted streams, Boulder Creek (Colorado) and Fourmile Creek (Iowa). A liquid chromatography/tandem mass spectrometry method was used to quantify antidepressants, including fluoxetine, norfluoxetine (degradate), sertraline, norsertraline (degradate), paroxetine, citalopram, fluvoxamine, duloxetine, venlafaxine, and bupropion in all three sample matrices. Antidepressants were not present above the limit of quantitation in water samples upstream from the effluent outfalls but were present at points downstream at ng/L concentrations, even at the farthest downstream sampling site 8.4 km downstream from the outfall. The antidepressants with the highest measured concentrations in both streams were venlafaxine, bupropion, and citalopram and typically were observed at concentrations of at least an order of magnitude greater than the more commonly investigated antidepressants fluoxetine and sertraline. Concentrations of antidepressants in bed sediment were measured at ng/g levels; venlafaxine and fluoxetine were the predominant chemicals observed. Fluoxetine, sertraline, and their degradates were the principal antidepressants observed in fish brain tissue, typically at low ng/g concentrations. A qualitatively different antidepressant profile was observed in brain tissue compared to streamwater samples. This study documents that wastewater effluent can be a point source of antidepressants to stream ecosystems and that the qualitative composition of antidepressants in brain tissue from exposed fish differs substantially from the compositions observed in streamwater and sediment, suggesting selective uptake.

Antidepressants at environmentally relevant concentrations affect predator avoidance behavior of larval fathead minnows (Pimephales promelas)

The effects of embryonic and larval exposure to environmentally relevant (ng/L) concentrations of common antidepressants, fluoxetine, sertraline, venlafaxine, and bupropion (singularly and in mixture) on C-start escape behavior were evaluated in fathead minnows (Pimephales promelas). Embryos (postfertilization until hatching) were exposed for 5 d and, after hatching, were allowed to grow in control well water until 12 d old. Similarly, posthatch fathead minnows were exposed for 12 d to these compounds. High-speed (1,000 frames/s) video recordings of escape behavior were collected and transferred to National Institutes of Health Image for frame-by-frame analysis of latency periods, escape velocities, and total escape response (combination of latency period and escape velocity). When tested 12 d posthatch, fluoxetine and venlafaxine adversely affected C-start performance of larvae exposed as embryos. Conversely, larvae exposed for 12 d posthatch did not exhibit altered escape responses when exposed to fluoxetine but were affected by venlafaxine and bupropion exposure. Mixtures of these four antidepressant pharmaceuticals slowed predator avoidance behaviors in larval fathead minnows regardless of the exposure window. The direct impact of reduced C-start performance on survival and, ultimately, reproductive fitness provides an avenue to assess the ecological relevance of exposure in an assay of relatively short duration.

Psychosocial work environment and antidepressant medication: a prospective cohort study

BackgroundAdverse psychosocial work environments may lead to impaired mental health, but it is still a matter of conjecture if demonstrated associations are causal or biased. We aimed at verifying whether poor psychosocial working climate is related to increase of redeemed subscription of antidepressant medication.MethodsInformation on all antidepressant drugs (AD) purchased at pharmacies from 1995 through 2006 was obtained for a cohort of 21,129 Danish public service workers that participated in work climate surveys carried out during the period 2002–2005. Individual self-reports of psychosocial factors at work including satisfaction with the work climate and dimensions of the job strain model were obtained by self-administered questionnaires (response rate 77,2%). Each employee was assigned the average score value for all employees at his/her managerial work unit [1094 units with an average of 18 employees (range 3–120)]. The risk of first-time AD prescription during follow-up was examined according to level of satisfaction and psychosocial strain by Cox regression with adjustment for gender, age, marital status, occupational status and calendar year of the survey.ResultsThe proportion of employees that received at least one prescription of ADs from 1995 through 2006 was 11.9% and prescriptions rose steadily from 1.50% in 1996 to the highest level 6.47% in 2006. ADs were prescribed more frequent among women, middle aged, employees with low occupational status and those living alone. None of the measured psychosocial work environment factors were consistently related to prescription of antidepressant drugs during the follow-up period.ConclusionThe study does not indicate that a poor psychosocial work environment among public service employees is related to prescription of antidepressant pharmaceuticals. These findings need cautious interpretation because of lacking individual exposure assessments.

Trace Analysis of Antidepressant Pharmaceuticals and Their Select Degradates in Aquatic Matrixes by LC/ESI/MS/MS

Treated wastewater effluent is a potential environmental point source for antidepressant pharmaceuticals. A quantitative method was developed for the determination of trace levels of antidepressants in environmental aquatic matrixes using solid-phase extraction coupled with liquid chromatography-electrospray ionization tandem mass spectrometry. Recoveries of parent antidepressants from matrix spiking experiments for the individual antidepressants ranged from 72 to 118% at low concentrations (0.5 ng/L) and 70 to 118% at high concentrations (100 ng/L) for the solid-phase extraction method. Method detection limits for the individual antidepressant compounds ranged from 0.19 to 0.45 ng/L. The method was applied to wastewater effluent and samples collected from a wastewater-dominated stream. Venlafaxine was the predominant antidepressant observed in wastewater and river water samples. Individual antidepressant concentrations found in the wastewater effluent ranged from 3 (duloxetine) to 2190 ng/L (venlafaxine), whereas individual concentrations in the waste-dominated stream ranged from 0.72 (norfluoxetine) to 1310 ng/L (venlafaxine).

Pargyline conjugate-induced long-term activation of monoamine oxidase as an immunological model for depression.

We describe an animal model of long-term depression based on active immunization of albino rats against BSA-conjugated inhibitor of monoamine oxidase, antidepressant, pargyline. Immunization resulted in anti-pargyline antibody formation and significant activation of monoamine oxidase A in brain. Immunized rats demonstrated potent decrease of motor, orientation and exploratory activity, increase of the immobility time ("despair") in Porsolt test, as well as notable signs of fear and anxiety in elevated plus maze. The cognitive processes were not significantly affected: the speed of learning with negative and positive reinforcement was not diminished. Complex effect on craving for alcohol (long-term suppression after short-term increase) was also demonstrated. The long-term (more than 45 days) depression achieved in this model makes it potentially important tool for testing new antidepressant pharmaceuticals.