Strategies for the detection, removal and elimination of antidepressants

ABSTRACT Sedentary lifestyle, malnutrition and intense work hours resulting in high stress are challenging the human mind and psychology. Many people are genetically predisposed, but many, unfortunately, are unable to withstand this life and need professional support. Although technology is produced to make life easier, in practice it causes many people to live outside the border. Antidepressants, which are used as a result of professional support, benefit in the short term, but they cause serious damage to environmental and aquatic life on the invisible side of the iceberg due to personal waste, irregular use and overdose. If there is no follow-up and environmental removal, all non-target creatures other than humans will be damaged in a very short time, and hence this damage will return to the human being, like a boomerang. Although many methods have been developed for the treatment of these types of pollutants today, it is clear that new agents and methods should be developed that will enable mobile study in natural environment where the pollution emerges. Accordingly, the aim of this review is to make a critical analysis of studies on the determination, removal, and elimination of antidepressants in recent years and to inspire future studies.


Introduction
Thousands of new chemical substances are produced every day in advanced technological laboratories to facilitate human life [1].While the industrial products, personal care materials and medicines produced serve people to improve the quality of life, on the other hand, the emergence of new ailments and diseases puts life in a vicious circle [2][3][4].Plastic bottles, nylon bags, other packaging products and cosmetic materials used for beautification are released to nature as waste (Figure 1).
People who want to gain health use medication, and a variable but important part of the pharmaceuticals they used is excreted through urine or faeces [6,7].Disposal and/or incorrect disposal of expired or unused medicines has led to substantial losses regarding health and financial state as opposed to the pharmaceutical industry with an income of more than $1000 billion in the past two decades [8,9].Today, tons of about 3000 different pharmaceutics are produced annually [10].Pharmaceutical effluents are come from domestic sewage, pharmaceutical manufacturing industry, animal husbandry, and mainly hospitals [11][12][13].In addition to no appropriate guidelines regarding the permissible limits of these pollutants, almost one-tenth of emerging contaminants, almost half of 64% of which is removed, cannot be removed by traditional methods available [14].Although some of these pollutants are permanent and therefore accumulate in water and the environment [15], some are called 'semi-permanent'.Despite their short half-lives, removal of these pollutants is constantly compensated by the arrival of new ones resulting in permanent background concentration [16] (Figure 2).It has been observed that this concentration can often be depends on the socio-economic life and climate [11], but no fully transparent and global study has been encountered that deals with local concentrations of the individual drugs.(reprinted with a permission from [5]).
There are very few studies comparing pharmaceutical concentrations to a safe drinking limit [17,18].Toxic effects of pharmaceutically active compounds (PhACs) are always observed on all forms of life [11,[19][20][21][22][23][24][25].Additionally, since chronic effects because pharmaceuticals have significantly occurred on ecosystems even if this pharmaceutics are in trace amounts, prediction of all long-term effects on the aquatic environment is challenging [26][27][28].Not only antimicrobial resistance but also effects on embryonic cells are because of increased ecotoxicological effects of these drugs [29][30][31][32][33]. PhACs also exhibit totally different effects independent to their expected activity as well as environmental toxicity [34].For example, pharmaceutical residues, which can be toxic in general, even at very low concentrations, are not only carcinogenic but also a great danger for human life, as well as their effects on the endocrine system [29,35,36].The presence of pharmaceutics residues even at trace concentrations (ng/L) has gained special attentions [37,38].For example, reproductive cycle of fishes is effected by the hormones used for birth control [39].In addition, additional toxicity comes from chemicals formed after incomplete mineralisation [40,41].Drug residues are resistant to biological degradation resulting in great difficulties in removal of complex structures [42].This can be attributed to the fact that treatment systems are mainly focused on removing biodegradable substances [1,16,[43][44][45].There is variety of techniques on detecting these compounds at trace amounts that can increase over time in all kind of water sources [39,46].Very little percent of recently prescribed drugs (<10%) are available regarding ecotoxicological data.Moreover only a few of them are subject to ecological risk assessment, which is the case to be considered as soon as possible [47].These pollutants can be treated by alternative methods like advanced oxidation processes (AOP) [43,48].
Antidepressants, which is only one of the industrially used micro-pollutants that are considered harmful for the environment, is used in the treatment of various psychological disorders, especially depression [49].There are many types of antidepressants, especially monoamine oxidase inhibitors (MAOIs) and tricyclic antidepressants (TCAs), which show high doses of high toxicity [50,51] (Table SF-1).For example, carbamazepine, a TCA, has a half- life of 36 hours and causes chronic toxicity [16].Considering that there is direct relation between carbon dioxide production and the number of people, unfortunately, the number of people using antidepressants is rapidly increasing in today's living conditions, which are a source of stress and depression.Depression is a major problem for about three hundred million people at all ages, which makes a significant contribution to the overall global burden of disease [52].Its uncontrolled use and overdose has many side effects, from sedation and acute extrapyramidal reactions to cardiovascular effects [53] (Figure 3).Antidepressants, are the most frequently detected -the first being in the sewage water in the 1970s-drugs in the water environment since they are frequently prescribed drugs [54,55].Especially TCAs, their usage has increased recently, are widely detected in surface water [56].Not only the critical biological activity but also the environmental resistance of the psychoactive drugs and their metabolites are the major issues [29].Adverse effect of antidepressants on aquatic life have studied in literature many times [57][58][59][60].Depending on the dose of TCAs used, mortality is inevitable due the direct effects on central nervous system and blocking neuro-endocrine signal [59,61].
In fact, the results of COVID-19, which has limited our lives and closed everybody to homes in recent days, will increase the number of people who are depressed, which is expected to result in more antidepressants use.In addition, there is a need to study environmental status and future of almost all psychiatric drugs like amitriptyline (AMI) because of very little or no information [58].In addition, due to the accumulation and permanence of these drugs in nature, there is a need for high-quality studies providing valuable data for compounds varying in structure, especially ionic compounds, to improve the removal, detection and elimination techniques used [62][63][64].

Basic strategies for drug residuals in aqueous media
Removal efficiencies are effected largely by any change in the structure because of dependent properties based on the very sensitive relation with the chemical structure of PhACs [65].Because the long-term use of these drugs on species different than which is not expected to use is not fully established considering the effects, the methods must be designed very well.Although many researches have done on the removal of PhACs via various processes, parameters and the behaviour of the aqueous matrix are not properly addressed on the success of removal (elimination or detection) of processes [66][67][68].
Aquatic-plant-based systems with a very long history has been shown as an alternative to traditional waste water treatment plants (WWTP) and has been actively used to effectively remove various pollutants including nitrogen, total suspended solids, phosphorus, microbial pollutants and heavy metals [69][70][71][72].However, detailed studies on removal paths are not yet available, but also no enough information for removal efficacy or purification performance.There is a limited number of reports on adsorption and degradation processes such as microbial or phytodegradation degradation [73,74], which are simultaneously occurring very complex processes [75][76][77][78].Additionally, presence of vegetation, plant species, and wetland configuration have effects on removal process resulting in the process-enhancement necessity [65,79,80].
So far, there is no regulation of acceptable drug levels, except for the advice of only a few scientists [36,45,81].Removal of PhACs can be performed via adsorption, AOPs, moving bed bioreactor (MBBR) and membrane bioreactor (MBR), etc.However, MBR and MBBR are time consuming and some toxic PhACs may kill microorganisms.Contaminated mud resulted from adsorption that may pollute the environment if not properly disposed of [82][83][84][85][86][87].While adsorption is good at removing organic pollutants, the secondary wastes they produce reduce their effectiveness [88][89][90] (Figure 4).Adsorbent concentration, pH, and salinity (ionic strength) are some of the matrix parameters designating the adsorption Figure 3.A schematic summary for side effects of overused antidepressant and antipsychotic drugs (reproduced with a permission from .[53] capacity [91].In addition to being insufficient in adsorption of emerging contaminants (ECs), regeneration of commonly used high-cost activated carbon (AC) may cause some additional environmental issues [92,93].The membrane technology used has superior capabilities in removing traces of micro-pollutants, including ECs, but most of the time membrane filtration processes is expensive due to frequent contamination and backwashing requirements [14,91,92,94].
Since water treatment plants are not sufficient sometime for the removal of some pharmaceuticals via conventional methods, AOPs is something new developed in recent years, with applications such as ozonation, Fenton-based processes, photocatalysis, UV/H 2 O 2 oxidation and non-thermal plasma [37,95].Low-cost AOPs are valuable candidates for pre-treatment process without waste that can increase the biodegradability of refractory compounds prior to biological treatment [96].AOPs produce strong oxidising radicals through light, heat, electricity and certain catalytic substances.PhACs are degraded and mineralised in a short time by releasing AOPs in water containing pollution [97].Ozonation is method producing high performance for the removal of various PhACs [98].However, one of the drawbacks limiting the commercial application of this technique is the high energy consumption in addition to the toxicity of PhACs underwent partial oxidation [14,98].Iron salts react with hydrogen peroxide to produce hydroxyl radicals, called Fenton-type reactions [99,100].As one of the AOPs, Fenton-type reactions are simple in operation and safe.Additionally, reagents used in this technique have almost no risk to the environment.Short Fenton-type reactions also provide no limitations regarding mass transfer [101][102][103].Mackulak and others have reported successful removal of 13 drugs from a WWTP in concentrations below the detection limit with Fenton and Fenton-like processes [104].
The Fenton process have biodegradation potential for persistent pollutants in wastewater coming especially from hospitals and drug production industry, therefore it can an ideal pretreatment set-up [105,106].Optical techniques and chemical probe measurements have proven that non-thermal liquid-contact plasma and gas-liquid media produces oxidising species to break down organic pollutants [107][108][109][110][111][112][113].Water pollutants are separated from plasma through different mechanisms by all oxidising species.Organic compounds are the main target and reactions with organic compounds are leading reaction [114].There are some other approaches described recently like degradation by mushroom enzymes [115,116].The application of electrochemical methods can also be used in the process of removing large particles from the water during the traditional treatment and preparing the system for the main application [117].Electrochemical methods are very simple and suitable for variety of chemicals, and thus cost-effective.
Detection of pharmaceuticals with column systems such as high performance liquid chromatography (HPLC) or gas chromatography (GC) can usually be performed qualitatively and quantitatively using various detectors [118].The sample preparation process in the HPLC system is easier than in GC, because the aqueous solution of sample prepared is filtered directly without being injected into the system (usually 0.45 mm filter).Physical and chemical properties of target chemicals are the determining parameters in method selection [119].Other methods used in pharmaceutical analysis include Raman spectroscopy [120,121], nuclear magnetic resonance [122] and electrochemical methods [123,124].The biggest limiting factor here is sample preparation procedures for these systems.Usually, the liquid-liquid extraction and microextraction, solid-phase extraction and microextraction are used to extract, purify and concentrate the samples.Although the sample preparation process is the limiting factor in column systems, combination of mass spectroscopy (MS) with HPLC or GC spend efforts to overcome this drawback by pulling the limit of determination of pharmaceuticals to ng/L levels [117].

Detection/Quantification strategies for drugs
Fluoxetine (FLX), venlafaxine (VEN) and vortioxetine (VTX) are effective antidepressants acting through different mechanisms used mainly in the treatment of obsessive compulsive and major depressive disorder (MDD) (Figure 5) [125][126][127][128][129]. As a second-generation antidepressant, VEN has similar effects with FLX.These drugs are usually metabolised by breaking down in the liver.Metabolites -these metabolites are also auxiliary to the treatment-of these drugs such as o-desmethylvenlafaxine (ODV) and norfluoxetine (NFLX) with a long half-life should also be monitored [130].VTX is a new type of antidepressant drug that is highly metabolised with a multimodal mechanism of action.However, metabolites of this drug have no contribution to the main activity of itself [131].Therapeutic drug monitoring (TDM) is attracting attention especially in neurology and psychiatry in determining patients' phenotype [132].Although it has been tried with different methods before [133][134][135], limitations such as high necessity of amount of sample, long and complex sample preparation, low sensitivity, and long run-time have rendered these methods dysfunctional.Kertys et al have determined VTX, FLX, VEN with their active metabolites in human plasma via a sensitive and simple LC-MS/MS method [136].In the study, different modification of different columns and different organic carriers were tested to get the best performance.The best result was achieved with Acquity UPLC BEH C18 column, and in both water and acetonitrile solutions with the use of 0.05% formic acid.Flow rate and total run time were determined as 0.4 mL/min and 4.2 min, respectively.Retention times were 1.03, 1.51, 2.19, 2.26 and 2.37 min for ODV, VEN, NFLX, FLX and VTX, respectively.Precipitation of proteins and phospholipids removal are achieved in human plasma using 96-well plate in a single step, but the preparation process is still complicated.Precision and accuracy method were increased using internal standards (ISs), deuterium-labelled analytes.Samples from MDD patients and from the patients medicated with one of the antidepressants were analysed through the method developed and, which were validated according to the latest European Medicines Agency (EMA) guidelines [137].Moreover, intra-and interday precision values are in between 0.3% and 9.6%, which is among acceptable limits.Although 4.2 minutes of runtime was obtained, the limit of detection (LOD) and limits of analysis remained at ng/mL level.For analysis of trace amount antidepressants, the LOD should be at femtogram/L or at least at ng/L levels.Additionally, not only many of these methods are prone to interferences because of sample preparation and manipulation but also they are limited to colourless and clear solution [138].Ketamine (KT), which is the main component of K Powder, is a colourless, tasteless and odourless drug.Besides being used as an anaesthetic in medicine, it has an effect that can produce a wide variety of sedative effects [139].It was most-wanted drug about 50 years ago shortly after its commercial production, resulting in being known as 'club drugs'.A victim cannot notice if someone added this chemical to a drink.After taking the drug, victim will suffer from sedation and amnesia.Ketamine-addicted people is very common worldwide to be treated [140][141][142][143].In addition, the aeration pool in urban WWTPs also acts as an active aerosol emitter during wastewater treatment operations [144,145].During the aeration process, harmful compounds, especially those with volatility, can be adsorbed onto suspended solids or microorganisms, while it also can be transferred to the air through bubbles that explode at the air-liquid interface.This means that these harmful chemicals can be transported kilometres away [146].In addition, WWTP are not always sufficient for the removal of these medicines and thus residues contaminate all kind of water sources, especially drinking water.To illustrate, drug residues detected in drinking water are in alarming amounts [147,148].Considering the abuse and potential ketamine-contaminants of WWTPs, ketamine determination is essential.For the determination of such a harmful chemical, Fu et al. combined molecular imprinting and electrochemical sensor technology to determine ketamine in human urine [149].They obtained molecularly imprinted polymer (MIP)-based membrane with UV-induced polymerisation with methacrylic acid as a monomer.Crosslinking was achieved using ethylene glycol dimethacrylate.They have used screen-imprinting method via modification with a metalorganic framework/graphene nanocomposite (MOFs@G).Relatively rough surface of the screen-printed electrode (SPE) provides high quality adhesion and thus simple formation of imprinted membranes without complex pretreatment, while also increasing the stability of the sensor [150].Being cheap and easy integration has made it a feasible for largescale applications as well.Highly selective and sensitive sensor has long-term stability according to the experimental results.The low detection limit (4.0 × 10 −11 mol/L) was achieved in a dynamic range from 1.0 × 10 −10 to 4.0 × 10 −5 M. In addition to the high selectivity offered by molecular imprinting, the use of graphene and MOF together led to dual-signal amplification resulting in high sensitivity.Increasing surface area with MOFs@G modification has also increased the effective binding potential, resulting in good results in complex biological samples considering selectivity, detection limits and linearity.However, methods such as centrifugation used in the MOF preparation process are the weakness of the method considering energy and time.Also, working at high temperatures means energy loss.Another handicap is the high sensitivity to oxygen encountered during organometallic UV polymerisation and different radical formations that occur afterwards, followed by the risk of heterolytic bond cleavage [151].It is necessary to determine how other molecules are affected in the applied UV wavelength.The most decisive factor in electrochemical sensors is that the film thickness should be adjusted very well.While the thickness is high, the conductivity decreases, otherwise the imprinting is not efficient [152].
It is accepted that antipsychotic drug therapy is one of the most effective approaches for schizophrenia [153] resulting in death more than many known diseases did.The efficacy of amisulpride used for this purpose has been proven with a low risk of side effects [154].However, there is a big range of pharmacokinetic variability depending on differences between individuals [155,156].Amisulpride concentration levels can be in between 0.010 and 1682 μg/mL [157].Therefore, TDM is vital for personalising the drug therapy and optimising the drug safety [158].An automated online SPEx method was combined with HPLC by He et al to determine trace amisulpride in human plasma, taking into account variables such as reliability, precision, and cost efficiency to meet large-scale routine quantification demand [159].A durable and reusable restricted-access media (RAM) column (Capcell Pak MF Ph-1) was used to prevent access (shielding) of macromolecules and to make highly efficient amisulpride determination.Efficient use of time (10 min) in the study can be attributed to the simultaneous run of two programmable pumps.In order to provide continuous analysis of large-scale samples, the removal of contamination in the RAM column, which prevents column contamination, was provided with appropriate valve replacement time.The method without any internal standard (IS) showed low detection limit (0.0035 μg/mL), satisfactory sensitivity and accuracy (98.1-106.6%recovery with standard deviations below 4.6%).RAM briefly allows the direct injection of plasma or serum online by preventing large molecules from reaching the internal adsorption sites in chromatographic systems with an analytical column [160].There is a stationary phase in RAM that divides analytes or holds them through ionic interactions.Since outer surface is generally composed of a non-adsorptive and hydrophilic porous polymer, low-mass-substances are retained and larger agents such as proteins are eluted from the excluded volume [161].As an advantage, there is no negative effect of individual differences on the accuracy without using IS observed in plasma samples obtained from four patients.In addition to its superiority considering speed, precision, requirement of IS, and automation compared to other methods [162-164], detection was achieved in a shorter time (12 min).Disadvantages such as low sensitivity, long run time, laborious and time-consuming process provided by HPLC system are largely eliminated by using RAM.
There are studies showing that sertraline (SER), which can be found in wastewater over 100 ng/L and accumulate in tissues at μg/g levels, is also present in environmental waters [166][167][168][169][170][171][172][173].In addition, this pollutant can also accumulate at μg/L levels in invertebrates and show toxic effects [174,175].SER transformation products (TPs) containing metabolite norsertralin (norSER) and sertraline ketone (SEK) have also been reported to be potentially persistent in water [176,177].Sample preparation through SPE is inevitable considering complexity of environmental matrices containing very low-level of SER residues.In the study, where Koler et al selected SER as the target compound, the selective binding properties of MIP sorbents to structural analogues of a target analyte were investigated.Additionally, parent compound was isolated simultaneously with the metabolites and TPs [178].One of two MIPs were chosen after SPE was best in terms of binding and one prepared in solvent and the other prepared by two-stage polymerisation.The main goal in applying a two-stage polymerisation is to increase the accessibility of the imprinted reaction sites.The first polymerisation has acrylic acid (AA) as monomer and divinyl benzene (DVB) as crosslinker providing a significant amount of free double bond that is not consumed in polymerisation [179].The polyDVB prepared in this way was also treated first with swelling solvent and porogen (toluene), and then with AA in the presence of radical initiator.Typically, porous polymers with a good degree microporosity are formed providing a high specific surface area [180].AA was grafted (copolymerised) to have acid-base interaction with SER.AA without methyl group undergoes automatic accelerated polymerisation resulting in modified polymer morphology to get increased recognition ability [181].Therefore, high binding rate was achieved for the first MIP-bound norsertralin and SEK.The imprinting factor for the second MIP for SER was the highest.Despite many efforts using solvents of different physical and chemical properties, target compounds could not be removed completely from MIPs polymerised in solvent.Concentration of SER was above the instrumental LOQ (54.3 ng/mL).Detection of SER at environmental concentrations was impossible because of electrostatic interaction between polymer and target molecule depending on continuous leakage.Therefore, the polymers were tested for binding of norSER and SEK.MIPs polymerised in solvent causes SER-leak from the imprinted cavities.In contrast, removal of SER was achieved under the LOQ via synthesised MIPs by a two-step polymerisation approach.Extraction of samples containing SER and norSER can be achieved by alternative commercial sorbents at different success rates [182][183][184][185].
Quetiapine (QTP), marketed as Seroquel, is one of the leading antipsychotic drugs in market for 20 years.QTP is active for cases from insomnia to schizophrenia and even posttraumatic stress disorder [186,187].While the maximum amount of QTP to be taken daily is 750 mg, it can be lethal when the therapeutic concentration reaches to 7 mg/L [188].Widespread abuse risk has led many analysts to develop simple, fast, and inexpensive techniques for QTP detection [189].Therefore, selective determination of QTP was performed by Motaharian et al. through a MIP-based carbon paste electrode by electrochemical sensor [190].In the study, precipitation polymerisation was used for the synthesis of MIP nanoparticles.According to the result obtained by optimised parameters, the QTP concentration in the suggested sensor was ranged from 1.6 to 250 (x 10 − [8]) M (R [2] = 0.9964) show linear responses.LOD and LOQ were found as 5.04 × 10 −9 and 16.8 × 10 −9 M, respectively.In addition, the RSD% amounts for the repeatability and reproducibility values of sensor were obtained as 2.19 and 3.02%, respectively.QTP in human serum was detected in its pharmaceutical formulation via this method.CPEs are frequently used by researchers considering desired chemical, physical and application properties such as simple modification, appropriate electrical conductivity, low cost and construction simplicity [189].However, challenges in developing enhanced analytical features such as sensitivity, selectivity, stability, and detection limit serve as driving forces in finding new generation agents for the modification during the design electrochemical sensors in sensing applications [190].Table SF-2 gives some recent studies for the detection drugs.

Removal strategies for drugs
Pharmaceutical products and their active compounds consumed by humans and animals are considered as highly harmful chemicals due to their persistence in the environment and biological activities [191].It is characterised by pollution that varies depending on consumption and efficiency in WWTP that are not specifically designed to remove PhACs [191,192].One of these pollutants, FLX is an antidepressant which is widely used by people in the treatment of depression and stable against environmental effects [193][194][195].Most (and their metabolites) can access domestic wastewater, as only a portion of it is metabolised.Silva et al. compared waste-based and commercial biosorbents considering adsorption of pharmaceuticals [196].While the adsorption capacities to FLX gave results in favour of commercial adsorbents, commercial adsorbents were more expensive than low-cost biosorbents considering per gram of removed FLX.Additionally, maximum adsorption performance of commercial adsorbents was higher than low cost bio-based counterparts.Here, the economy/performance balance needs to be well estimated and the main aim must be definite.According to the result obtained, it is reported that SCG was the most economical while it was determined that the second most suitable adsorbent was cork waste since SCG did not produce any waste during preparation.It is clear that the higher surface area of AC with micro pore volume than that of zeolites results in higher adsorption capacity of FLX.Because, FLX (pKa = 9.8) is positively charged and adsorbents have the opposite at neutral and relatively higher pH (7,9) resulting in maximum adsorption capacity.Therefore, the electrostatic interactions in between were affected by the ambient pH as expected.At pH values below pKa, the FLX molecule is essentially positively charged, but both ionised and non-ionised forms are present at the same ratio at pH equal to pKa.Since acidic pH provide a proton-rich environment for both biosorbents and commercial adsorbents resulting in positive charges surrounding both structures, the low adsorption capacity obtained at these pH values is an expected result.Since the positive charge amount on the surface is less than the situation at pH 2, the higher adsorption performance was achieved than the obtained at pH 2, despite the positively charged surface of commercial adsorbents ad pH 7.
High operational costs required for the application of an adsorbent in wastewater treatments systems result in limited application for the adsorption process which is effective for the removal of pharmaceuticals [197,198].Biochar materials can be promising solution upon the need for cheaper alternatives [199][200][201].Therefore, Fernandes et al investigated the adsorption of FLX to different biomass [202].Removal of FLX was performed by twelve renewable biochar adsorbents obtained from forest and agri-food waste.According to preliminary adsorption experiments, Quercus ilex, Cydonia oblonga, Eucalyptus, Juglans regia and Vitis vinifera was found as the best among these twelve.The maximum adsorption capacity achieved at the 15-minute equilibrium time was determined as 6.41 mg/g at 500°C for Eucalyptus, which is better than the fishbone biochar at 600°C (2.52 mg/g).As can be seen, although it offers a lower adsorption performance than that of commercially available counterparts [203,204], the biochars used as alternative for the removal of FLX can be considered low-cost adsorbents.Hydronium and hydroxide ion concentration in the environment is the most effective factor considering the electrostatic interactions between functional groups of adsorbent and adsorbate [205].Therefore, FLX adsorption performance of adsorbent varied depending on pH values.Considering that the pKa of FLX (9.8) and the pHpzc (9.59) of all tested biochars are high, the molecules are positively charged for all the pH values (pH <pK a ) examined [203], so the electrical repulsion between adsorbent and adsorbate was inevitable in the pH range (5.5-9.5)applied.Decrease in pH increases the repulsion [203], but the best results have been achieved for eucalyptus biochar below pH: 7 with maximum electrostatic repulsion.In this case, this is not the main factor affecting adsorption kinetics.Some functional groups on the biochar surface lose their protons with increased pH and are negatively charged, resulting in positive effects on adsorption [203].Another FLX removal study was performed by Sousa-Moura et al through zebrafish embryos.They have used these embryos as a biosensor.Hydrophilic carbon nanotubes (CNT) and AC were combined to obtained hybrid micro/nano-structured carbon-based material (HMNC) for the removal of FLX in wastewater [206].These types of fish are often used to investigate the ecotoxicity of micropollutants, as they are subjected to a small and rapid development [207,208].It is well known that PhACs can be removed from wastewater using AC.The physiochemical properties (Particle size, surface area, and pore size distribution) are designating the types of AC available.The functional group distribution on its surface is the first-degree determining factor in the interaction of AC with contaminants.The long incubation times required for effective adsorption and difficult reactivation of AC are the most obvious disadvantages [209][210][211].Zebrafish embryos are not affected by the toxicity of AC and HMNC (LC 50 > 1000 mg/L), so fatality or lethal effects can be reduced to great extend in FLX-containing culture matrix by adding HMNC.The HMNC-FLX interaction and exposure of the embryo to them are not harmful to zebrafish at the concentrations used.This is an indication that the adsorption medium is safe.Based on the adsorptive feature of HMNC, removal of a significant amount of FLX in the medium allows for a good development of zebrafish embryo in the environment.Despite low specific surface are (SSA), adsorption performance of HMNC towards FLX is better than that of AC at low concentrations (10 mg/L).This can be attributed to different interaction behaviour of FLX with AC and HMNC based on their different electronic nature.Covering the surface of AC with CNTs in the HMNC composite enhances existing feature and creates new ones.Synthesis procedure results in defect on CNTs and adds functional groups [212,213] to interact with the amino group of FLX.Therefore, FLX molecules are masked and zebrafish embryos cannot reach easily.No behavioural changes of zebrafish embryos observed in FLX@HMNC environment can be attributed to that adsorption of FLX molecules to the HMNC is higher than to AC at higher concentrations (100 mg/L).This result agrees with the information for HMNC in water that there is no toxic effect observed for HMNC without FLX to zebrafish based on the micro/nanostructured nature of CNTs rather than being free particles.
Neuropathic pain and depression can be treated commonly by nortriptyline (NT) [214].Sadri et al. used kaolinite, montmorillonite and gibbsite as adsorbents for the removal of NT [148].Adsorption of NT was not affected from the electronic nature of solution in between pH 3 and pH 12.While maximum adsorption capacities were achieved for the montmorillonite (19.3 μmol/m [2]) and kaolinite (6.4 μmol/m [2]) at pH 6.0, gibbsite show relatively less adsorption performance towards NT.Dominating forces were electrostatic and hydrophobic interactions during the adsorption.However, almost no effect by the hydronium ion concentration in the medium can be attributed to the hydrophobic nature of adsorbent (KGa-2, SWy-3 and gibbsite) and adsorbate (NT).Below pKa of NT, negatively charged groups on the SWy-3 and KGa-2 are active and promotes electrostatic interaction in pH below pK a at which molecules are protonated and thus.High concentration of NT results in the formation of aggregates.Electrostatic interaction is dominating during adsorption of larger aggregates on the montmorillonite based on additional positively charged groups they have, whereas hydrophobic interaction is leading because of reduction of net charge on the adsorbed complex.Interaction on the surface of kaolinite is weaker based on the smaller charge intensity on the surface.There are also about two times more hydrophobic sites on montmorillonite.On the contrary to the case montmorillate, adsorption of NT on the surface of kaolinite requires mostly hydrophobic interaction.Based on their hydrophobic character, organic aggregates are more favourable in aqueous solutions.These aggregates are adsorbed based on this dual character behaving as a template.Adsorption of substituted anilines and benzylamines on montmorillonite is happening based on significantly intermolecular cation-π interactions [215].The π system is provided by adsorbed-compound and is the cation by amine group on adjacent molecule.Such cation-π interactions can be a model for the adsorption of NT system accumulated on the surface of hydrophobic substrates such as montmorillonite and kaolinite.While the aggregates in the solution are likely to adsorb, results obtained in this study cannot separate whether adsorption of aggregates on the surface or aggregation via adsorption of NT to the molecules already adsorbed.AMI is common in the treatment of psychotic disorders mainly anxiety and depression [216].Although membrane bioreactors are used to achieve removal of approximately AMI of 98% [217], non-biodegradable AMI of 100% is still reported even after treatment in some WWTPs [218,219].Tsai et al. has performed AMI-removal via palygorskite clay (PFl-1) [220] and found the surface adsorption of 0.168 mmol/g AMI to the PFl-1 by cation exchange mechanism in 15-minute equilibrium time in solution of pH 6-7.They determined this value compatible not only with the Langmuir isotherm, but with pseudo second order kinetic.Palygorskite is in the fibrous form composed of magnesium-aluminium phyllosilicate structures.Size of AMI was found to be too big to fit the channel size provided by palygorskite and sepiolite [221,222].Therefore, adsorption of AMI can be on the outer surface of palygorskite, strip-like structure of which is ideal for interaction with AMI.Temperature and ionic strength are not effective on removal of AMI.Precipitation was the leading factor for the removal of AMI at high pH instead of adsorption.Overall, PFl-1 presented good adsorption behaviour towards AMI in from wastewater.

Elimination strategies for drugs
Antidepressant SER, which can be metabolised in the liver, has a basic metabolite called N-desmetylsertraline or norSER.Concentration of both SER and norSER in wastewater can be in the ng/L [166, 182,223], and even in these quantities, SER is a harmful chemical for many organisms in terms of vital activities such as locomotor activity and feeding behaviour [174,224,225].Because of poor biodegradability and hydrolytic stability of SER, it is mainly eliminated by photodegradation [226,227].TPs are formed during degradation processes.The chemical structures of TPs and its metabolites emerges in the human body are not necessarily the same, therefore, real structure and their formation kinetics should be defined first for the evaluation of environmental risks.Jakimska et al performed SER's photodegradation experiments by use of natural solar irradiation through a xenon lamp, but there was no valid results about the effects of different water matrices, except for autocatalytic reactions occurring in the photodegradation mixture [228].Gornik et al. have conducted the first study on the photodegradation of these drugs in wastewater and norSER formation under the specific conditions.They tried to reveal whether phototranformation kinetics of SER were affected by the direct or indirect photolysis.TP formation via photochemical reactivity measurements in laboratory systems aiming to measure kinetic parameters was also investigated [229].Although natural samples are used, the desired performance cannot be obtained due to various external variables difficult to include in laboratory conditions [230].Therefore, modelling photo reactivity in deep water may help to understand the photochemical behaviour of natural waters.Moreover, some independent variables such as quantum yields are also required for better understanding.It is better to focus on accuracy instead of similarity to surface water dynamics [231].In this study, the laboratory and natural conditions are followed in parallel, laboratory measurements and estimation results of photoreactivity parameters were compared with SER behaviour in river under sunlight resulting in confirmation of modelling.Based on these variables, the photochemical degradation of SER was estimated in natural water source.As the OH• source, nitrate was chosen because rate constant for the OH•reaction gives better predictions than that nitrite gives.SER degradation rate was decreased by the addition of 2-propanol (2-P), which behave like OH• scavenger, to the reaction mixture.Another reason for this can be the competition between SER and 2-P for hydroxyl radical reaction.Photodegradation of SER was performed by MP lamb and by solar radiation (natural sunlight) which is two-three times slower (daytime) during the laboratory-scale setup based on overall irradiation energy reaching the samples.
Imipramine (IMI), the first TCA, is used extensively to manage hyperactivity and phobic disorders, and is continually produced industrially as the Gold Standard [232,233].Xie et al. used the vacuum ultraviolet (VUV) system to eliminate IMI, common in the water environment [234], and also evaluated some factors that affect IMI degradation kinetics.Changes in acute toxicity were investigated based on intermediate products during IMI degradation.Although some highly toxic intermediates were produced, their transformation to other low toxic products was investigated.The initial reactions were proposed based on the splitting of the side chain and the degradation pathways (which are hydroxylation of iminodibenzyl and methyl groups) and intermediates identified by LC/ MS.Despite more toxic first intermediates than IMI, further oxidation to low-toxic products is possible.
Increasing the pH of the solution from 5.0 to 9.0 resulted in improved IMI degradation.As the pH increases from 5.0 to 7.0, a rather small increase in rate of IMI degradation is well suited to the percentage of proton-free IMI.Higher quantum efficiencies for proton-free IMI can be explained by easier stimulation of some proton-free compounds by light radiation of electrons on amine groups [235].It is believed that the lower degradation efficiency of IMI in realistic water primarily depends on the photon block and the consumption of HO• by natural organic matter.Formation of organic intermediates as a result of gradual decrease of the total organic carbon concentration during the IMI degradation in the VUV system results eventually in mineralisation to CO 2 .In other words, CO 2 is the ending molecules in IMI degradation pathway in this system.The L/L 0 value sharply dropped from 1.0 to 0.2 at shorter reactions taking the time of 5 minutes or less resulting in formation of the initial intermediates with significant acute toxicity, even higher than IMI.However, the L/L 0 value began to increase after first five minutes for the reactions taking longer time resulting in conversion of intermediate products with high acute toxicity to other compounds with lower acute toxicity.
Duloxetine (DUL) is a drug used in common anxiety disorders and major depression by acting as selective serotonin-norepinephrine reuptake inhibitor (SNRI) (Figure 6).DUL became the seventh best-selling prescription drug under the Cymbalta brand in 2013, selling $5 billion in the USA.[236].There is limited information on the formation DUL's TPs in water sources.Osawa et al. simulated possible abiotic environment using distilled water under controlled experimental conditions through hydrolysis and photodegradation [237].Eleven TPs were generated, nine of which were obtained under UV light and two of which were from chlorine contact.Quadrupole time-offlight (TOF) MS-combined ultra HPLC was used for the detection.The nine TPs were analysed for the determination of chemical structures by analysis of fragmentation models in MS/MS spectra.Complete degradation of the parent compound was achieved during photodegradation and chlorination in 30 minutes and 24 hours, respectively.Therefore, complete degradation of DUL was achieved in both processes.In hydrolysis, the drug was stable for 4 days without any TP.After the 45 minutes of photodegradation, all TPs were disrupted.Contrary to partial elimination of TP-332, chlorination was effective for the degradation of TP-290 in 24 hours.Complete degradation of almost all TPs were achieved during the experiment.While it was found that only a few TPs of DUL produces more ecotoxicity than the DUL itself, positive mutagenicity was observed for six TPs.Analysis of wastewater samples revealed the uncomplete removal of the DUL in the WWTP and probable formation TP-332 during chlorination.Investigation of the possible existence of these TPs should be the subject of future studies considering the toxicity of these chemicals by in vitro and in vivo analysis.
AMI, which is detected in natural waters, is a commonly used TCA and have harmful potential towards aquatic organisms [56,58,[239][240][241].Wan et al. use simulated sunlight to investigate the synergy between iron(III) containing citrate (Cit) and oxalate (Ox) system during degradation [242].Photodegradation of AMI was performed via iron(III)-Cit-Ox and (iron(III)-Cit and iron(III)-Ox) systems with respect to carboxylate concentration and pH.It was found that carboxylate concentration has positive relation with the photodegradation of AMI in iron(III)- Ox in media with pH: 3.5 at the ratio of 10:120-10:150 (mM) Fe(III)/oxalate [243][244][245].On the contrary it given the highest performance at neutral pH under simulated sunlight.While photodegradation has inverse relation with pH in the iron(III)-Ox system, efficiency increases in order of decreasing pH except for pH 3.0 which is lower than pH 5 in the iron(III)-Cit system.In the case of the iron(III)-Cit-Ox system, mostly same inverse relation is dominating such as decreasing photodegradation with increasing pH.However, photodegradation have accelerated with the addition of oxalate to the Fe(III)-citrate system.Synergy was the highest at almost neutral pH and positively correlated with the the concentration rates of oxalate to citrate.Photo production of OH was optimised at mildly acidic pH (around pH:5.0) with the ratio of 10:150-10:300 (mM) iron(III)/Cit in the iron(III)-Cit system [246][247][248][249].Nonetheless, the domination kinetic during indirect photodegradation of AMI was pseudo first-order kinetics in the iron(III) containing carboxylate environment.Approximately 90% removal was achieved at pH 6.0 at 30 minute in the iron(III)-Cit-Ox system and dibenzosuberone was formed.Removal or degradation of organic pollutants can be successful with the cooperative effect of the binary iron(III)-Cit-Ox system.Identification of photo products of AMI are performed using LC-MS.
Risperidone is used in the treatment of schizophrenia and bipolar mania [250].Kamali et al. aimed to remove risperidone by microspheres through supercritical carbon dioxide (scCO 2 ) [251].Since carbon dioxide has low critical temperature (32.1°C) and pressure (7.38 MPa), it is used as supercritical liquid with the advantageous features such as being non-flammable and cheap etc.Moreover, it is relatively non-toxic [252].Preparation of microspores was held on via a conventional emulsion evaporation procedure and a supportive method of super critical CO 2 (scCO 2 ) [253] after evaporation, eliminated the residual (dichloromethane) DCM.Inhalation of DCM may cause neurotoxicity or teratogenicity.To achieve maximum percent elimination efficiency, central composite design was applied using parameters such as pressure, temperature, and static and dynamic time.Headspace GC-FID was used for the analysis of residual DCM after scCO 2 treatment.LOD and LOQ for DCM were 7.31 and 21.93 μg/mL, respectively.A GC (Shimadzu 2010 Plus) was used with flame ionisation detector through the DB-5 MS column having the helium flow rate of 30 mL/min (carrier gas).The steps required to obtain the appropriate mathematical data required both a competent staff and highly complex applications.Considering the temperatures used, it was not an energy efficient operation.Maximum DCM elimination was achieved at the static and dynamic time of 21.31 and 119.17 min, respectively, using scCO 2 (99.43%).During this process pressure was 226.44 bar under the temperature of 44.77°C.Application of scCO 2 decreased the DCM content of risperidone-PLGA microspheres from 4612 ± 198 to <21.93 μg/mL.Moreover, scCO 2 treatment also have increasing effect on the average particle size and pore diameter.Increase in the porosity depending on the scCO 2 have the drug distributed homogenously in the matrix.The pre-scCO 2 process contains a polymeric chain and thus a greater amount of solvent, which can increase drug release resulting in the continuous release of the drug.Because DCM is a non-polar material, it dissolves well in scCO 2 and thus removal of DCM from the microsphere matrix was successful.Elimination rate of organic solvent changes depending on tensile strength, density, solubility and viscosity of scCO 2 , changing with the temperature and pressure.In addition, the systems used to obtain scCO 2 are quite disadvantageous regarding energy consumption.Moreover, optimising the contact of the sample materials with the supercritical fluid is critical to increase scCO 2 efficiency.Solvent-sample contact time can be affected by the dynamic and static times.In this study, while saturation solubility was achieved at 21.31 minutes of static time, saturation solubility of DCM in scCO 2 was not effected much by higher static times [254].

Critics and Future Prospects
Pharmaceutics and some personal care products (PPCPs) containing pharmaceutic chemicals have been widely used with the increase of complexity of modern life resulting in environmental problems, especially in aquatic world [255,256].Pharmaceutical residues found in all kinds of water sources are a global issue, even in drinking water.The main sources of pharmaceutics and PPCPs are human by excretion, improper disposal of unused drugs, drug industry and hospitals [45,256].Additionally, WWTPs are insufficient considering total removal [166, [257][258][259].Despite their very low amounts (even ng/L) in the aquatic environment, they are active in organisms in water and thus humans through drinking water.They also have synergy with chemicals around resulting in enhanced mode of action and thus increased toxicity [233,255,[260][261][262][263] (Figure 7).Antidepressants, which is the hero of modern stressful world with the increasing number of depressive patients, are leading chemicals among the micropollutants in the aquatic matrix.Researchers pay more and more attention recently for the detection of these chemicals depending on the concerns on the risks and hazards to primarily human and the environment [45,233,[264][265][266].However, TPs emerging after interaction of a pharmaceutical compound with biotic and abiotic factors in the environment may behave totally different from the original compound depending on the changed physical and chemical properties resulting in change in toxicity degree and persistence power [267][268][269].Although, institutes such as the Water Framework Directive [270] and Unregulated Contaminant Monitoring Regulation [271] are monitoring some micropollutants in Europe and USA, respectively, there is still lack of regulatory laws in all around the world for safe drug concentrations.
Low efficiency of treatment of drinking water results in decrease of eater quality and thus potential risks for living things depending on the acute toxicity of antidepressants [256,260,272,273].Therefore, advanced technologies urgently need to be developed for better efficiencies.AOPs are very effective for degradation of organicbased micropollutant, providing reactive hydroxyl and sulphate radicals [66,97,274].As one of AOPs, photochemical process (UV/persulphate, UV/H 2 O 2 , UV/chlorine etc.) is a kind of sustainable and environmentally friendly method in addition to being sustainable for effective degradation of antidepressants [262,263,[275][276][277][278][279][280][281][282][283][284].However, remaining oxidants or catalysts after reactions results in further environmental concerns.
As a result, the work done so far is not particularly cost-friendly, requires expensive complex analysis devices, and the need for experienced staff is a serious obstacle in this field as in almost every study.In addition, there is incomplete information regarding the structural similarities, chemistry and emerging metabolites of unknown antidepressants for the elimination and determination.The absence of analysis in the natural environment, the impossibility of deducing cooperative effects, common ion and molecule effects and trace amounts that can occur in that environment put these studies in the shade, although they are excellent.In this sense, it is necessary to establish a special team especially for the development of mobile, precise and accurate devices with low detection limit.This team should be the top priority for us to design a device that can make online analysis in this direction as a team including mechanical, electronic and computer engineers, and chemists, biologists and mathematicians that works together.

Conclusion
As seen from the reviewed studies, pharmaceutical micro-pollutants are the most threatening elements of today.In fact, these pollutants, like a pin-pulled bomb, are a threat to the whole world because they are persistent and cause worldwide pollution.Structural similarities and the absence of functional groups in some of them make their determination quite difficult.Although every method has an advantage, perhaps it has more deficiencies and limitations than positive sides.Therefore, as scientists, we earn almost one percent of what we spend in pollution studies.New systems should be developed immediately, and even universities should have departments that only train micro-pollution specialists.The development of special analysis devices that can only work in this area may be a good long-term solution.Of course, the most important of these is the consumption of these drugs as little as possible and their controlled disposal.Information should also be given for disposal, and even people using medicines should be trained.The management of governments for a special disposal method for pharmaceutical pollutants like recycling bins designed for paper, glass and pet bottles can also be a solution in many respects.

Figure 1 .
Figure 1.The vicious cycle of emerging micro-pollutants that are frequently exposed in daily life.(reprintedwith a permission from[5]).

Figure 2 .
Figure 2. Pharmaceutics from water sources to living things.

Figure 4 .
Figure 4. Several advantageous features of adsorption technique.

Figure 5 .
Figure 5. A) Structures of FX and intermediates and B) Structures of NFX and intermediates.(reprinted with a permission from [165]).

Figure 6 .
Figure 6.Chemical structure of DUL and its degradation products I-X, XII-XIII, XV-XVII (reprinted with a permission from [238]).