The effects of antidepressants appear to be rapid and at environmentally relevant concentrations

The effects of antidepressants on wildlife are currently raising some concern because of an increased number of publications indicating biological effects at environmentally relevant concentrations (<100 ng/L). These results have been met with some scepticism because of the higher concentrations required to detect effects in some species and the perceived slowness to therapeutic effects recorded in humans and other vertebrates. Because their mode of action is thought to be by modulation of the neurotransmitters serotonin, dopamine, and norepinephrine, aquatic invertebrates that possess transporters and receptors sensitive to activation by these pharmaceuticals are potentially affected by them. The authors highlight studies on the effects of antidepressants, particularly on crustacean and molluskan groups, showing that they are susceptible to a wide variety of neuroendocrine disruptions at environmentally relevant concentrations. Interestingly, some effects observed in these species can be observed within minutes to hours of exposure. For example, exposure of amphipod crustaceans to several selective serotonin reuptake inhibitors can invoke changes in swimming behavior within hours. In mollusks, exposure to selective serotonin reuptake inhibitors can induce spawning in male and female mussels and foot detachment in snails within minutes of exposure. In the light of new studies indicating effects on the human brain from selective serotonin reuptake inhibitors using magnetic resonance imaging scans, the authors discuss possible reasons for the discrepancy in former results in relation to the read-across hypothesis, variation in biomarkers used, modes of uptake, phylogenetic distance, and the affinity to different targets and differential sensitivity to receptors.

[1]  Fiona M Lyng,et al.  Aquatic ecotoxicity of the selective serotonin reuptake inhibitor sertraline hydrochloride in a battery of freshwater test species. , 2009, Ecotoxicology and environmental safety.

[2]  Jacob K Stanley,et al.  Aquatic ecotoxicology of fluoxetine. , 2003, Toxicology letters.

[3]  John P. Sumpter,et al.  The Read-Across Hypothesis and Environmental Risk Assessment of Pharmaceuticals , 2013, Environmental science & technology.

[4]  E. Furlong,et al.  Selective uptake and biological consequences of environmentally relevant antidepressant pharmaceutical exposures on male fathead minnows. , 2011, Aquatic toxicology.

[5]  S. Peroutka,et al.  The molecular evolution of G protein-coupled receptors: Focus on 5-hydroxytryptamine receptors , 1994, Neuropharmacology.

[6]  P. Fong,et al.  The biological effects of antidepressants on the molluscs and crustaceans: a review. , 2014, Aquatic toxicology.

[7]  C. Metcalfe,et al.  Analysis of paroxetine, fluoxetine and norfluoxetine in fish tissues using pressurized liquid extraction, mixed mode solid phase extraction cleanup and liquid chromatography-tandem mass spectrometry. , 2007, Journal of chromatography. A.

[8]  C. Metcalfe,et al.  Pharmaceuticals and Endocrine Disruptors in Wastewater Treatment Effluents and in the Water Supply System of Calgary, Alberta, Canada , 2006 .

[9]  E. Kravitz,et al.  Mapping of serotonin-like immunoreactivity in the lobster nervous system , 1983, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[10]  M. Servos,et al.  Antidepressants and their metabolites in municipal wastewater, and downstream exposure in an urban watershed , 2010, Environmental toxicology and chemistry.

[11]  J. Sze,et al.  Serotonin (5HT), Fluoxetine, Imipramine and Dopamine Target Distinct 5HT Receptor Signaling to Modulate Caenorhabditis elegans Egg-Laying Behavior , 2005, Genetics.

[12]  J. Sumpter,et al.  Quantitative Cross-Species Extrapolation between Humans and Fish: The Case of the Anti-Depressant Fluoxetine , 2014, PloS one.

[13]  J. Cook,et al.  A Theoretical Model for Utilizing Mammalian Pharmacology and Safety Data to Prioritize Potential Impacts of Human Pharmaceuticals to Fish , 2003 .

[14]  E. Furlong,et al.  Trace analysis of antidepressant pharmaceuticals and their select degradates in aquatic matrixes by LC/ESI/MS/MS. , 2008, Analytical chemistry.

[15]  M. Lürling,et al.  Changes in Ventilation and Locomotion of Gammarus pulex (Crustacea, Amphipoda) in Response to Low Concentrations of Pharmaceuticals , 2009 .

[16]  E. Thurman,et al.  Pharmaceuticals, hormones, and other organic wastewater contaminants in U.S. streams, 1999-2000: a national reconnaissance. , 2002, Environmental science & technology.

[17]  Alex T Ford,et al.  Anti-depressants make amphipods see the light. , 2010, Aquatic toxicology.

[18]  R. Brain,et al.  Toxicity and hazard of selective serotonin reuptake inhibitor antidepressants fluoxetine, fluvoxamine, and sertraline to algae. , 2007, Ecotoxicology and environmental safety.

[19]  T. Matsutani,et al.  In vitro effects of serotonin and prostaglandins on release of eggs from the ovary of the scallop, Patinopecten yessoensis. , 1987, General and comparative endocrinology.

[20]  S. Montgomery,et al.  A comparative review of escitalopram, paroxetine, and sertraline: are they all alike? , 2014, International clinical psychopharmacology.

[21]  J. Sumpter,et al.  The apparently very variable potency of the anti-depressant fluoxetine. , 2014, Aquatic toxicology.

[22]  R. Miledi,et al.  Blockage of muscle and neuronal nicotinic acetylcholine receptors by fluoxetine (Prozac). , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[23]  J. Zhan,et al.  Growth inhibition and coordinated physiological regulation of zebrafish (Danio rerio) embryos upon sublethal exposure to antidepressant amitriptyline. , 2014, Aquatic toxicology.

[24]  Alejandro J. Ramirez,et al.  Determination of select antidepressants in fish from an effluent‐dominated stream , 2005, Environmental toxicology and chemistry.

[25]  J. Sumpter,et al.  Are some invertebrates exquisitely sensitive to the human pharmaceutical fluoxetine? , 2014, Aquatic toxicology.

[26]  J. Sekizawa,et al.  The effects of pH on fluoxetine in Japanese medaka (Oryzias latipes): acute toxicity in fish larvae and bioaccumulation in juvenile fish. , 2008, Chemosphere.

[27]  Alex T Ford,et al.  Behavioural and transcriptional changes in the amphipod Echinogammarus marinus exposed to two antidepressants, fluoxetine and sertraline. , 2014, Aquatic toxicology.

[28]  C. Barata,et al.  Low environmental levels of fluoxetine induce spawning and changes in endogenous estradiol levels in the zebra mussel Dreissena polymorpha. , 2012, Aquatic toxicology.

[29]  B. Halling‐Sørensen,et al.  Environmental risk assessment of three selective serotonin reuptake inhibitors in the aquatic environment: A case study including a cocktail scenario , 2011, Environmental toxicology and chemistry.

[30]  R. Miledi,et al.  Blockage of 5HT2C serotonin receptors by fluoxetine (Prozac). , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[31]  D. Kolpin,et al.  Antidepressant pharmaceuticals in two U.S. effluent-impacted streams: occurrence and fate in water and sediment, and selective uptake in fish neural tissue. , 2010, Environmental science & technology.

[32]  L. Kux OF HEALTH AND HUMAN SERVICES Food and Drug Administration , 2014 .

[33]  S. Harzsch,et al.  Serotonin-immunoreactive neurons in the ventral nerve cord of Crustacea: a character to study aspects of arthropod phylogeny. , 2000, Arthropod structure & development.

[34]  C. Donly,et al.  Ancestry of neuronal monoamine transporters in the Metazoa , 2006, Journal of Experimental Biology.

[35]  P. Fong,et al.  Zebra Mussel Spawning Is Induced in Low Concentrations of Putative Serotonin Reuptake Inhibitors. , 1998, The Biological bulletin.

[36]  John A. H. Lee Health: United States , 1986 .

[37]  E. Michael Thurman,et al.  Response to Comment on “Pharmaceuticals, Hormones, and Other Organic Wastewater Contaminants in U.S. Streams, 1999−2000: A National Reconnaissance” , 2002 .

[38]  O. Berglund,et al.  Influence of pH-dependent aquatic toxicity of ionizable pharmaceuticals on risk assessments over environmental pH ranges. , 2015, Water research.

[39]  Todd Gouin,et al.  Routes of uptake of diclofenac, fluoxetine, and triclosan into sediment‐dwelling worms , 2016, Environmental toxicology and chemistry.

[40]  C. Chambliss,et al.  Aquatic toxicity of sertraline to Pimephales promelas at environmentally relevant surface water pH , 2009, Environmental toxicology and chemistry.

[41]  Human use pharmaceuticals in the estuarine environment: a survey of the Chesapeake Bay, Biscayne Bay, and Gulf of the Farallones , 2006 .

[42]  M. Lürling,et al.  Behavioural responses of Gammarus pulex (Crustacea, Amphipoda) to low concentrations of pharmaceuticals. , 2006, Aquatic toxicology.

[43]  Ludovic Dickel,et al.  Cryptic and biochemical responses of young cuttlefish Sepia officinalis exposed to environmentally relevant concentrations of fluoxetine. , 2014, Aquatic toxicology.

[44]  R. Croll,et al.  Serotonergic responses of the siphons and adjacent mantle tissue of the zebra mussel, Dreissena polymorpha. , 1999, Comparative biochemistry and physiology. Part C, Pharmacology, toxicology & endocrinology.

[45]  T. Clark,et al.  pH-dependent toxicity of serotonin selective reuptake inhibitors in taxonomically diverse freshwater invertebrate species , 2015 .

[46]  A. Kullyev,et al.  A Genetic Survey of Fluoxetine Action on Synaptic Transmission in Caenorhabditis elegans , 2010, Genetics.

[47]  Paola Valbonesi,et al.  The mode of action (MOA) approach reveals interactive effects of environmental pharmaceuticals on Mytilus galloprovincialis. , 2013, Aquatic toxicology.

[48]  Michel Boulouard,et al.  Effects of perinatal exposure to waterborne fluoxetine on memory processing in the cuttlefish Sepia officinalis. , 2013, Aquatic toxicology.

[49]  B. Brooks,et al.  Water Quality of Effluent-dominated Ecosystems: Ecotoxicological, Hydrological, and Management Considerations , 2006, Hydrobiologia.

[50]  P. Fong,et al.  Antidepressants (venlafaxine and citalopram) cause foot detachment from the substrate in freshwater snails at environmentally relevant concentrations , 2012 .

[51]  B. Brooks Fish on Prozac (and Zoloft): ten years later. , 2014, Aquatic toxicology.

[52]  H. Horvitz,et al.  Mutations in the Caenorhabditis elegans Serotonin Reuptake Transporter MOD-5 Reveal Serotonin-Dependent and -Independent Activities of Fluoxetine , 2001, The Journal of Neuroscience.

[53]  Laura N. Vandenberg,et al.  Hormones and endocrine-disrupting chemicals: low-dose effects and nonmonotonic dose responses. , 2012, Endocrine reviews.

[54]  J. Thomas-Oates,et al.  Fate and Uptake of Pharmaceuticals in Soil–Earthworm Systems , 2014, Environmental science & technology.

[55]  C. Gagnon,et al.  Determination of basic antidepressants and their N-desmethyl metabolites in raw sewage and wastewater using solid-phase extraction and liquid chromatography-tandem mass spectrometry. , 2008, Analytical chemistry.

[56]  Á. N. Chonchubhair Selective serotonin reuptake inhibitors. , 1998, Anaesthesia.

[57]  D. H. Edwards,et al.  A crustacean serotonin receptor: Cloning and distribution in the thoracic ganglia of crayfish and freshwater prawn , 2004, The Journal of comparative neurology.

[58]  D. Margulies,et al.  Serotonergic Modulation of Intrinsic Functional Connectivity , 2014, Current Biology.

[59]  M. J. Barry Effects of fluoxetine on the swimming and behavioural responses of the Arabian killifish , 2013, Ecotoxicology.

[60]  Alex T Ford From gender benders to brain benders (and beyond!). , 2014, Aquatic toxicology.

[61]  Niranjan Rao,et al.  The Clinical Pharmacokinetics of Escitalopram , 2007, Clinical pharmacokinetics.

[62]  R. Bagby,et al.  The Hamilton Depression Rating Scale: has the gold standard become a lead weight? , 2004, The American journal of psychiatry.

[63]  Pirow,et al.  The sites of respiratory gas exchange in the planktonic crustacean daphnia magna: an in vivo study employing blood haemoglobin as an internal oxygen probe , 1999, The Journal of experimental biology.

[64]  Edward E. Ruppert,et al.  Invertebrate Zoology: A Functional Evolutionary Approach , 1974 .

[65]  Rik Oldenkamp,et al.  Do concentrations of ethinylestradiol, estradiol, and diclofenac in European rivers exceed proposed EU environmental quality standards? , 2013, Environmental science & technology.

[66]  J. Thomas,et al.  Fluoxetine-resistant mutants in C. elegans define a novel family of transmembrane proteins. , 1999, Molecular cell.

[67]  S. Stahl Not so selective serotonin reuptake inhibitors. , 1998, The Journal of clinical psychiatry.