Social anxiety disorder (SAD) is characterized by fear and avoidance of social interactions and situations in which an individual is being the focus of attention. This current thesis aims to examine the efficacy of pharmacological treatment, particularly selective serotonin reuptake inhibitors (SSRIs) in individuals with a generalized social anxiety disorder (gSAD) in comparison with placebo (no active medication). In this systematic review, Scopus and Web of Science were searched for relevant research regarding the efficacy of the SSRI medication (paroxetine, sertraline, fluvoxamine and escitalopram) in comparison with placebo. Sixteen articles were included in this analysis. Results demonstrated that SSRI medication has greater efficacy in comparison with placebo both in short- and long-term time, prevent relapse in the long-term treatment of SAD and had a beneficial effect on different areas of individuals life's such as work, performance, romantic relationships etc.

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Selective serotonin re-uptake inhibitors (SSRIs) are a class of anxiolytic and anti-depressant drugs. SSRIs act on the evolutionarily ancient serotonergic system which is virtually identical throughout the vertebrate phylum. Serotonin is involved in a wide range of processes ranging from neuronal and craniofacial embryonic development to regulation of behaviour. However, SSRIs are also emerging pollutants, mainly entering the environment via sewage treatment plants. Since the serotonergic system is virtually identical in humans and other animals, exposed animals will be affected in similar ways as humans and suspicions are rising that ecologically important behaviours may be affected in subtle ways. Using the three-spined stickleback (Gasterosteus aculeatus) and zebrafish (Danio rerio) as model organisms, this thesis focuses on the behavioural effects of SSRIs in fish. The SSRI used throughout this thesis is citalopram, which has been found in fish in coastal areas of the Baltic Sea and other parts of the world. Effects on behaviour were investigated using several different tests measuring stress response, feeding behaviour, aggression and locomotor activity. Anxiolytic effects of 0.1 μg/l, 1.5 μg/l 15 μg/l were investigated as well as effects of 0.15 μg/l and 1.5 μg/l on feeding behaviour. Because serotonin is involved in the development of the nervous system, the effects of developmental exposure to 1.5 μg/l was studied after 100 days of remediation. Finally, because SSRIs rarely occur alone in natural waters, the effects on zebrafish of citalopram in a cocktail scenario, with the anxiogenic compound 17α-ethinyl estradiol (EE2 ) was also investigated. Citalopram was found to have anxiolytic effects on the three-spined stickleback at 0.1 μg/l, 1.5 μg/l and 15 μg/l. Citalopram also suppressed feeding behaviour within a week of exposure and at concentrations as low as 0.15 μg/l. Developmental exposure to 1.5 μg/l for 30 days was found to increase aggression and feeding behaviour and to reduce locomotor activity. The changes were persistent and remained in adult fish. In the cocktail scenario, citalopram in single-substance exposure had anxiolytic effects on one parameter in the novel tank test at 0.1 μg/l. Citalopram enhanced the anxiogenic effects of EE2 in the novel tank test, but in the scototaxis test citalopram appeared to counteract the effects of EE2. It is concluded that citalopram has the potential to affect behaviour in fish at concentrations that have been found in close proximity of sewage treatment plants. / Det serotonerga systemet är i stort sett identiskt hos människor och övriga vertebrater. Serotonin är inblandat i ett stort antal kroppsliga funktioner, bland annat stressreaktioner, reglering av födobeteende och aggression. Vidare är serotonin med och reglerar nervsystemets tillväxt under embryonalutvecklingen. Selektiva serotoninåterupptagshämmare (SSRI) är en grupp antidepressiva och lugnande läkemedel vars användning har ökat snabbt på senare år då de är effektiva och har få allvarliga bieffekter. SSRI verkar på det serotonerga systemet, genom att blockera återupptaget av serotonin i den presynaptiska nervänden. SSRI har tilldragit sig en viss uppmärksamhet som potentiella miljöhot då de visats kunna påverka ekologiskt relevanta beteenden hos fisk och andra akvatiska organismer vid relativt låga koncentrationer i miljön samtidigt som de bryts ned dåligt i avloppsreningsverk. Avhandlingen fokuserar på ekologiskt relevanta beteendeeffekter av SSRI på fisk, med storspigg (Gasterosteus aculeatus) och zebrafisk (Danio rerio) som modellorganismer. Citalopram har använts som försökssubstans då det anses vara den SSRI som har minst antal sidoeffekter på till exempel det dopaminerga systemet. Citalopram förekommer i utloppsvatten från reningsverk i alla industrialiserade länder och har även hittats i abborre i Östersjön. Effekter av exponering för SSRI har påvisats med hjälp av olika beteendetest. Skototaxi-test och novel tank diving test mäter stressresponsen genom att kvantifiera preferensen för närhet till botten och mörka omgivningar. Ätbeteende har mätts som antal utfall mot en matbit under en given tidsperiod och aggression har mätts genom att räkna antal bett mot en spegel. Anxiolytiska effekter undersöktes vid koncentrationer på 0,1 µg/l, 15 µg/l och 1,5 µg/l. Effekter på ätbeteende undersöktes vid 0,15 µg/l och 1,5 µg/l. Eftersom serotonin är inblandat i embryonalutvecklingen testades de beteendemässiga effekterna av exponering för 1,5 µg/l under utvecklingen. Då citalopram sällan förekommer ensamt i miljön testades ett cocktailscenario där zebrafisk samtidigt exponerades för citalopram och den anxiogena substansen 17α-etinylestradiol (EE2). Citalopram befanns ha anxiolytisk verkan på storspigg samt undertrycka ätbeteendet. Effekter på ätbeteendet uppstod inom en vecka efter exponering och vid den minsta testade dosen vilken var 0,15 µg/l. Storspigg som exponerats under embryonalutvecklingen var mer aggressiva, hade lägre lokomotoraktivitetoch gjorde fler utfall mot mat då de testades 100 dagar efter att exponeringen avslutats. Samtidigt exponering för citalopram och den anxiogena substansen 17α-etinylestradiol (EE2) gav tvetydiga resultat. Citalopram ensamt hade ingen signifikant påverkan på beteendet i detta försök. I skototaxitestet motverkade citalopram den anxiogena effekten av EE2 medan det förstärkte den anxiogena effekten i novel tank. Sammanfattningsvis har citalopram effekter på ekologiskt relevanta beteenden hos fisk i koncentrationer som förekommer i ytvatten. Det har också permanenta effekter på beteende om exponeringen sker under embryonalutvecklingen. Dessa resultat gör det sannolikt att citalopram och andra SSRI har ekologiska effekter i påverkade vattendrag.

Denna studien har gjorts på blåmusslor, Mytilus edulis trossulus, för att undersöka effekter av det antidepressiva läkemedlet Citalopram på blåmusslans fysiologiska funktioner. Blåmusslan är en vanligt förekommande art i Östersjön där den fungerar som en nyckelart som; bidrar till den biologiska mångfalden, är långt ner i näringskedjan och är anpassningsbar. Dessa egenskaper gör den även lämpad som testorganism i denna studie. Citalopram är ett av Sveriges vanligaste läkemedel för att behandla psykisk ohälsa och den verkar genom att blockera återupptaget av serotonin i hjärnan och ingår i läkemedelsgruppen serotoninhämmare (SSRI). Serotonin påverkar flera olika funktioner i kroppen såsom rörelseförmåga, sinnesstämningar och mättnadskänsla. Läkemedel inklusive Citalopram återfinns i sjöar och vattendrag, detta för att läkemedel inte renas bort i våra reningsverk och för att det idag inte finns några krav på läkemedelsrening i svenska avloppsreningsverk. Läkemedel tillverkas för att vara aktiva vid låga koncentrationer vilket gör att de även har en negativ effekt på marina organismer. I denna studie har vi analyserat effekter av Citalopram på blåmusslans fysiologiska funktioner genom tre analyser, filtrering, rörelse och produktion av byssustrådar i tre olika koncentrationer (0 ng/l, 20 ng/l och 200 ng/l). Analyserna utfördes under två tidsperioder, exponering av läkemedel under 96 timmar samt remediering utan läkemedel under 72 timmar. Studien visar en signifikant skillnad i filtrering (P-värde = 0.04416) mellan grupperna under exponeringen där fler blåmusslor som var exponerade för 200 ng/l visade en lägre filtreringsaktivitet (fler individer var helt stängda). Under remedieringen observerades en signifikant högre mortalitet bland blåmusslor som exponerats för 200 ng/l (P-värde = 0.01347). Blåmusslor exponerade för 200 ng/l Citalopram visade även en lägre produktion av byssustrådar (P-värde= 0.02702). I den här studien kan vi se att läkemedlet Citalopram har en negativ påverkan på flera av blåmusslans fysiologiska funktioner. / The aim of this study was to investigate the effects of the antidepressant drug Citalopram on blue mussels, Mytilus edulis trossulus, in the Baltic Sea. The blue mussel is a common species that is considered a key species in the Baltic Sea as it contributes to biodiversity, and is adaptable which makes it suitable as a test organism in this study. Selective serotonin reuptake inhibitors (SSRIs) are the most commonly prescribed antidepressants and a common SSRI substance is Citalopram. This substance is one of Sweden's most common drugs for treating mental illness. Serotonin affects several different functions in the body such as movement, mood and saturation. Many pharmaceuticals including Citalopram are found in lakes and streams, this is because pharmaceuticals are not purified in our wastewater treatment plants and there is no requirements for filtration of pharmaceuticals in Swedish wastewater treatment plants as of today. Pharmaceuticals are manufactured to be active even at low concentrations, a negative side effect of this is that it is also active in the environment causing negative effects on marine organisms. In this study, we analyzed the effects of Citalopram on the physiological functions of the blue mussel by three analyzes; filtration, movement and production of byssus threads using three different concentrations (0 ng /l, 20 ng/l och 200 ng/l) of Citalopram. The analyzes were carried out over two time periods, exposure of drugs for 96 hours and remediation without drugs for 72 hours. The study shows a significant difference in filtration (P-value = 0.04416) between the groups during exposure, where more blue mussels that were exposed to 200 ng/l showed a lower filtration activity (more individuals completely closed). During the remediation, a significantly higher mortality was observed among blue mussels exposed to 200 ng/l (P value = 0.01347). Blue mussels exposed to 200 ng/l Citalopram also showed lower production of byssus threads (P value = 0.02702). In this study we can see that the drug Citalopram has a negative effect on several of the blue mussel's physiological functions.

Bakgrund: Globalt drabbas 300 miljoner av depression och sjukdomen kan idag behandlas med både antidepressiva läkemedel och psykoterapi. Depression diagnosticeras utifrån klassificeringssystemen ICD-10 och DSM-5 och självskattats utifrån MADRS-skala. Sjukdomen kan delas in i följande svårighetsgrader: lätt/lindrig depression, medelsvår/måttlig depression och svår/djup depression. Vid val av antidepressiva läkemedel är det viktigt att ta hänsyn till svårighetsgrad, biverkningar och interaktioner.  Syfte: Syftet med denna studie är att kartlägga läkemedelslistor framtagna av Sveriges olika läkemedelskommittéer och beskriva val av läkemedelsbehandling vid depression för vuxna och äldre.  Metod: En dokumentanalys utfördes som lämpar sig till att kunna jämföra aktuell offentlig information. Datainsamlingen utfördes hösten 2022 med hjälp av Sveriges 21 olika regioners behandlingsrekommendationer för vuxna och äldre. En egen bedömningsskala med maximalt tre poäng utfördes för att lyckas bedöma regionernas läkemedelsrekommendationer.  Resultat: För vuxna rekommenderar 19 regioner vid lindrig-medelsvår depression sertralin, vid medelsvår-svår rekommenderar 13 regioner venlafaxin och vid svår rekommenderar sex regioner TCA där amitriptylin/klomipramin är mest förekomna. För äldre rekommenderar 13 regioner sertralin/mirtazapin/escitalopram vid lindrig-medelsvår depression, vid medelsvår-svår rekommenderar 13 regioner duloxetin/venlafaxin och vid svår rekommenderar två regioner duloxetin. Enligt den egna bedömningsskalan uppnås varierande antal poäng där totalt sju regioner uppnår maximal poäng.  Slutsats: SSRI var den vanligaste preparatgruppen som rekommenderades av regionerna vid medelsvår depression hos både vuxna- och äldre. Vid svår depression var den vanligaste preparatgruppen SNRI för äldre och TCA för vuxna. Enligt den egna bedömningsskalan var Läkemedelverkets och Socialstyrelsens rekommendationer mest vanligt förekomna källorna hos regionerna. / Background: Globally, 300 millions of people suffer from depression and the disease can today be treated with both antidepressants and psychotherapy. Depression is diagnosed from the classification system ICD-10 and DSM-5 and is self-assessed based on the MADRS-scale. The disease can be divided into the following difficulty level: light/mild depression, medium/moderate depression, and severe/deep depression. It is very important to consider difficulty level, side effects and interactions when choosing an antidepressant.  Aim: The aim of this study is to identify drug lists produced by Sweden’s different pharmaceutical committees and describe the choice of drug treatment for depression for adults and the elderly.  Materials and methods: A document analysis was performed which is suitable to be able to compare public information. The collection of data was performed autumn 2022 with the help of Sweden’s 21 different regions treatment recommendations for adults and the elderly. An own assessment scale was accomplished to judge the regions drug treatment recommendations. Results: For the adults, 19 regions primarily recommend sertraline for mild-moderate depression, for moderate-deep depression 13 regions recommend venlafaxine and for deep depression six regions recommend TCA where amitriptyline/clomipramine are most common. For the elderly, 13 regions primarily recommend sertraline/mirtazapine/escitalopram for mild-moderate depression, for moderate-deep depression 13 regions recommend duloxetine/venlafaxin and for deep depression two regions recommend duloxetine. According to the own assessment scale a varying number of points were achieved, were a total of seven regions achieved maximum points.  Conclusions: SSRIs were the most common drug group recommended by the regions for moderate depression for both adults and the elderly. In deep depression the most common drug group was SNRIs for the elderly and TCAs for adults. According to the own assessment scale the Swedish- Medicines Agency and Social Welfare Board are most common sources in the regions.

Major depressive disorder (MDD) is rapidly growing among the population. A widely believed neurobiological explanation is that the symptoms arise due to an imbalance of the neurotransmitter serotonin. Therefore, the most provided antidepressant is currently selective serotonin reuptake inhibitors (SSRI), which increase the serotonin in the synaptic cleft by inhibit the reuptake of serotonin. There are medications which challenge the serotonin hypothesis such as tianeptine. Tianeptine increases the reuptake of serotonin in the synaptic cleft and thus decreasing the serotonin levels. The thesis has three aims: First, to investigate what mechanisms tianeptine and SSRI work upon. Second, compare the efficiency of SSRI and tianeptine. Third, if the two agents display any differences in adverse side effects. A systematic review and search through relevant databases were made to obtain results. The main findings of this thesis were the two agents act differently of many aspects of the brain mechanisms and neurochemistry such as the cannabinoid system, expression of different cell types and their dependence of protein kinase. Even so, the results show that both agents are equally efficient in treating the depressive symptoms in the larger context, although some interesting findings are seen when zooming in. Anxiety is often comorbid with depression and even though both tianeptine and SSRI are shown to reduce these symptoms during chronic administration, SSRI can produce an anxiogenic effect in the beginning. Another noteworthy finding was that tianeptine showed to be clinically significant, but so did placebo. The third aim investigated the differences in side-effects between these two agents, and both agents were equally safe in number of adverse side-effects. Though tianeptine showed to have some slight advantages in manners of sexual dysfunction and the item 3 on the CGI scale.

Serotonin stimulates reproduction and inhibits feeding/growth in the neuroendocrine brain of goldfish. The objective of this thesis is to study the effects of selective serotonin reuptake inhibitor pharmaceuticals (SSRIs) on these systems, as SSRIs, such as fluoxetine, are detected in effluent and bioconcentrate in the brain of wild fish. Genes of the serotonin system were cloned to identify molecular conservation, seasonal expression, and tissue distribution. The serotonin transporter, the target molecule of fluoxetine, was highly conserved and ubiquitously expressed in goldfish. Seasonal changes of hypothalamic gene expression of the serotonin transporter support a role in the seasonal modulation of both processes. Fluoxetine injection experiments were used to assess effects on reproductive endpoints and to identify molecular mechanisms in the neuroendocrine brain. Fluoxetine inhibited serum estradiol concentrations in female goldfish and decreased isotocin mRNA abundance in the hypothalamus and telencephalon. Isotocin injections stimulated circulating estradiol concentrations, providing a causal link. Evidence for an involvement of serotonin in isotocin regulation was investigated using immunocytochemistry and 5-HT1A receptor agonists and antagonists. A close proximity of serotonin fibers and isotocin cell bodies and fibers was found in the telencephalon and pituitary,respectively. Injection of a 5-HT1A receptor antagonist inhibited isotocin mRNA expression in the telencephalon. Identified gene targets were investigated in waterborne fluoxetine exposures,including environmental concentrations. Waterborne fluoxetine led to a reduction in basal and pheromone-stimulated milt volume in male goldfish. Gene expression evidence indicated a central inhibitory effect of fluoxetine through the decrease in mRNA abundance of follicle-stimulating hormone in the pituitary and isotocin in the telencephalon. Feeding rate and weight decreased in fluoxetine-injected goldfish, indicating an anorexigenic effect. Fluoxetine induced changes in the gene expression of the feeding peptides neuropeptide Y, corticotropin-releasing factor, and cocaine- and amphetamine-regulated transcript-I in the hypothalamus and telencephalon. Waterborne exposure to fluoxetine validated the anorexigenic effect in goldfish and was correlated with increased expression of corticotropin-releasing factor mRNA, an anorectic peptide. The thesis provides evidence for disrupting effects of fluoxetine on neuroendocrine control of reproductive function and feeding/growth in goldfish, partially at environmental concentrations. The thesis provides the framework for the investigation of existing aquatic contaminants which modulate the serotonin system.

Serotonin stimulates reproduction and inhibits feeding/growth in the neuroendocrine brain of goldfish. The objective of this thesis is to study the effects of selective serotonin reuptake inhibitor pharmaceuticals (SSRIs) on these systems, as SSRIs, such as fluoxetine, are detected in effluent and bioconcentrate in the brain of wild fish. Genes of the serotonin system were cloned to identify molecular conservation, seasonal expression, and tissue distribution. The serotonin transporter, the target molecule of fluoxetine, was highly conserved and ubiquitously expressed in goldfish. Seasonal changes of hypothalamic gene expression of the serotonin transporter support a role in the seasonal modulation of both processes. Fluoxetine injection experiments were used to assess effects on reproductive endpoints and to identify molecular mechanisms in the neuroendocrine brain. Fluoxetine inhibited serum estradiol concentrations in female goldfish and decreased isotocin mRNA abundance in the hypothalamus and telencephalon. Isotocin injections stimulated circulating estradiol concentrations, providing a causal link. Evidence for an involvement of serotonin in isotocin regulation was investigated using immunocytochemistry and 5-HT1A receptor agonists and antagonists. A close proximity of serotonin fibers and isotocin cell bodies and fibers was found in the telencephalon and pituitary,respectively. Injection of a 5-HT1A receptor antagonist inhibited isotocin mRNA expression in the telencephalon. Identified gene targets were investigated in waterborne fluoxetine exposures,including environmental concentrations. Waterborne fluoxetine led to a reduction in basal and pheromone-stimulated milt volume in male goldfish. Gene expression evidence indicated a central inhibitory effect of fluoxetine through the decrease in mRNA abundance of follicle-stimulating hormone in the pituitary and isotocin in the telencephalon. Feeding rate and weight decreased in fluoxetine-injected goldfish, indicating an anorexigenic effect. Fluoxetine induced changes in the gene expression of the feeding peptides neuropeptide Y, corticotropin-releasing factor, and cocaine- and amphetamine-regulated transcript-I in the hypothalamus and telencephalon. Waterborne exposure to fluoxetine validated the anorexigenic effect in goldfish and was correlated with increased expression of corticotropin-releasing factor mRNA, an anorectic peptide. The thesis provides evidence for disrupting effects of fluoxetine on neuroendocrine control of reproductive function and feeding/growth in goldfish, partially at environmental concentrations. The thesis provides the framework for the investigation of existing aquatic contaminants which modulate the serotonin system.

Serotonin stimulates reproduction and inhibits feeding/growth in the neuroendocrine brain of goldfish. The objective of this thesis is to study the effects of selective serotonin reuptake inhibitor pharmaceuticals (SSRIs) on these systems, as SSRIs, such as fluoxetine, are detected in effluent and bioconcentrate in the brain of wild fish. Genes of the serotonin system were cloned to identify molecular conservation, seasonal expression, and tissue distribution. The serotonin transporter, the target molecule of fluoxetine, was highly conserved and ubiquitously expressed in goldfish. Seasonal changes of hypothalamic gene expression of the serotonin transporter support a role in the seasonal modulation of both processes. Fluoxetine injection experiments were used to assess effects on reproductive endpoints and to identify molecular mechanisms in the neuroendocrine brain. Fluoxetine inhibited serum estradiol concentrations in female goldfish and decreased isotocin mRNA abundance in the hypothalamus and telencephalon. Isotocin injections stimulated circulating estradiol concentrations, providing a causal link. Evidence for an involvement of serotonin in isotocin regulation was investigated using immunocytochemistry and 5-HT1A receptor agonists and antagonists. A close proximity of serotonin fibers and isotocin cell bodies and fibers was found in the telencephalon and pituitary,respectively. Injection of a 5-HT1A receptor antagonist inhibited isotocin mRNA expression in the telencephalon. Identified gene targets were investigated in waterborne fluoxetine exposures,including environmental concentrations. Waterborne fluoxetine led to a reduction in basal and pheromone-stimulated milt volume in male goldfish. Gene expression evidence indicated a central inhibitory effect of fluoxetine through the decrease in mRNA abundance of follicle-stimulating hormone in the pituitary and isotocin in the telencephalon. Feeding rate and weight decreased in fluoxetine-injected goldfish, indicating an anorexigenic effect. Fluoxetine induced changes in the gene expression of the feeding peptides neuropeptide Y, corticotropin-releasing factor, and cocaine- and amphetamine-regulated transcript-I in the hypothalamus and telencephalon. Waterborne exposure to fluoxetine validated the anorexigenic effect in goldfish and was correlated with increased expression of corticotropin-releasing factor mRNA, an anorectic peptide. The thesis provides evidence for disrupting effects of fluoxetine on neuroendocrine control of reproductive function and feeding/growth in goldfish, partially at environmental concentrations. The thesis provides the framework for the investigation of existing aquatic contaminants which modulate the serotonin system.

Pharmaceuticals, enter the aquatic environments through sewage treatment plants and may affect fish. This examination paper is a literature study that focuses on Selective serotonin reuptake inhibitors, SSRIs, exposure and the impacts on teleosts in the Baltic Sea by assessment of peer-reviewed literature and material. Teleosts affected by exposure of these substances may demonstrate physiologically as well as behavioral alterations. These can be observed as alterations in aggression, boldness, mobility, growth, feeding rate or in endocrine processes. The potential of which SSRI may effect teleosts depends on the pH of the aquatic environment, temperature, other contaminants and the fat solubility of the substances. Some effects caused by SSRI exposure may elicit ecological impacts. These particularly concern changes and effects in terms of evasiveness, reproductive capacity and ability to find food as well as alterations of interspecificity. Even the balance between population density, individual fitness and by extension survival might be affected. Effects in interspecificity may potentially lead to local extinctions and changes in food webs. Furthermore, results demonstrated that when a substance is bioaccumulated and the teleosts are eaten by predators on higher trophic levels, marine ecosystems can also be affected. Moreover a conclusion could be drawn the level of concentration of SSRIs in the aquatic environment may be of less significance since teleosts have the potential to bioaccumulate SSRIs in tissue over time and in this sense concentrations may reach harmful levels that can cause physiological or behavioural alterations. Continuous studies should refer to chronic tests studies with focus on a field testing environment for understanding of natural conditions and exposure. Furthermore, studies on how ecosystems may be affected should be important to give an overview of the problem with SSRI exposure. As the Baltic Sea is a sensitive environment, studies should preferable be made on species living in this environment.