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.

Selective serotonin reuptake inhibitors (SSRIs), like fluoxetine, are widely used to treat depressive disorders during pregnancy. These antidepressants reach water reservoirs through sewage treatment facilities and expose the aquatic vertebrates, including fish. It has been shown that early-life exposure to fluoxetine could disrupt the normal function of the stress axis by decreasing the level of circulating glucocorticoids in humans, rodents, and teleosts. Our lab recently showed that early life exposure to fluoxetine resulted in transgenerational hyporcortisolism and altered exploratory behaviour in adult male zebrafish and their descendant male adults for at least three generations. In the current study, we used a stress-responsive transgenic zebrafish line (SR4G) that expresses green fluorescence protein (eGFP) under the control of six consecutive glucocorticoid response elements. The effects of developmental exposure to fluoxetine on the transcriptional profiles of genes in the larval head and male adult telencephalon and hypothalamus were analysed using high throughput RNA sequencing. We also assessed the potential of eGFP mRNA to evaluate blunted stress response as an alternative to cortisol immunoassay measurements. The effects of bisphenol A, vinclozolin and fluoxetine were ytested in the SR4G line. Developmental exposure to fluoxetine resulted in a life-long dysregulation of pathways involved in nervous system development, stress response, and lipid metabolism in both larvae and adult zebrafish. Numerous differentially expressed genes in zebrafish are orthologous to genes in Homo sapiens linked the development of the major depressive disorder and epigenetics regulation and include bdnf, trkb, npas4, per1, per2, dnmt3a, adarb1, adaeb2, hdac4, hdac5, hdac8, and atf2. It is suggested that the dysregulation of the primary transcription regulators of circadian rhythm (clocka) and stress response (nr3c1), amongst others, were the potential drivers of the observed life-long effects. Furthermore, we report on a significant positive linear correlation between cortisol levels and eGFP mRNA levels in SR4G transgenic zebrafish larvae (R2> 0.9). Random forest and logistic regression models trained by eGFP mRNA levels both correctly predicted the blunted stress response. The negative predictive value (NPV) for both models was 100%. Models based on the mRNA levels of 11 genes associated with neurogenesis, stress response and depression resulted in a similar 100% NPV. These findings provide evidence for a life-long effect of developmental exposure to fluoxetine. This study also provides a proof-of-concept for an in vivo biomonitoring assay to screen chemicals for their stress-disrupting potential.

The purpose of this study was to investigate the relationship between selective serotonin reuptake inhibitor (SSRI) medication on auditory skills in clinically depressed subjects. Experimental subjects prescribed an SSRI were tested in a medicated and an unmedicated condition, and the test results were compared. Furthermore, the experimental group was compared with a control group consisting of normal subjects. Test measures included pure tone audiometry, tympanometry, acoustic reflex thresholds, and auditory electrophysiologic measures such as auditory brainstem and auditory late responses. An assessment scale for depression (Beck Depression Inventory-II) was also used. Results indicated statistically significant differences for the BDI-II between the control and experimental groups for both conditions. Electrophysiologic measures indicated a significantly shorter latency for auditory late potential P1 at 55 dBnSL, and a significantly larger amplitude at 45 dBnSL for the N1/P2 component for the unmedicated group. Although the other measures showed trends, they did not reach significance.

No description available.

Bakgrund: Depression är en vanligt förekommande psykisk störning som ungefär 280 miljoner människor i världen lider av. Det är ett tillstånd som påverkar individens livskvalité och som i värsta fall kan leda till självmord. Antidepressiva läkemedel, så som selektiva serotonin återupptagshämmare (SSRI), är förstahandspreparat till patienter som lider av depression. Fysisk aktivitet kan bidra till god hälsa och mildra depressiva symtom samt förebygga depression. Syfte: Syftet med detta examensarbete var att undersöka om fysisk aktivitet är jämförelsebar med antidepressivt läkemedel som behandlingsmetod mot depression. Metod: Examensarbetet är en litteraturstudie och relevanta artiklar söktes vid den medicinska databasen PubMed. För detta arbete valdes sammanlagt sju artiklar, fyra av dessa undersökte fysisk aktivitet i jämförelse med antidepressiva läkemedel som monoterapier samt tre artiklar vilka undersökte fysisk aktivitet som tilläggsbehandling. Resultat: I studie ett uppvisade alla grupper en statistisk signifikant reducering av depressionssymtomen, samtliga grupper uppvisade även en ökad remissionsfrekvens. Dock visade studien ingen statistisk signifikant skillnad mellan de aktiva behandlingsgrupperna gentemot placebo gällande reducering av depressionssymtomen. Resultaten från studie två och tre uppvisade en statistiskt signifikant skillnad med att förbättra depressionssymtomen mellan de aktiva behandlingsgrupperna jämfört med placebo. Studie fyra inkluderade ingen kontrollgrupp, intention-to-treat analysen uppvisade en statistisk signifikant skillnad mellan träning och antidepressiva läkemedel gällande att mildra depressionssvårigheten, fördel till träning. Dock förekom det ingen statistiskt signifikant skillnad i per-protocol analysen. Resultaten från studie fem till sju indikerar att träning som tilläggsbehandling uppvisar en positiv effekt med att mildra depressionssymtomen. Diskussion: Studie ett till fyra studerade behandlingsalternativen som monoterapi och konstaterade att fysisk aktivitet är likvärdig med antidepressiva läkemedel som behandlingsform mot depression. Resultaten från studie fem till sju bör tolkas varsamt då fysisk aktivitet inte undersöktes som monoterapi. Dock tyder resultaten på att träning som tilläggsbehandling har en god effekt för att reducera depressionssymtom. Studierna hade inte samma primär utfallsvariabel och det finns begränsningar med självskattningsskalor vilket kan påverka resultaten. Följsamheten för träning var låg vilket begränsar tolkningen av resultaten. Antidepressiva läkemedel ger fler biverkningar än fysisk aktivitet. Vidare forskning inom området behövs för att ge bättre följsamhet för fysisk träning och med kliniskt strukturerade intervjuer utförd av en legitimerad psykiatriker, för att fastställa diagnos och säkerställa resultat. Slutsats: Fysisk aktivitet uppvisar en god effekt mot att mildra depressiva symtom i likhet med antidepressiva läkemedel hos individer i medelåldern och äldre. Det är tänkbart att rekommendera fysisk aktivitet som förstahandspreparat i form av fysisk aktivitet på recept (FaR) för att öka följsamheten av aktivitet.

Bakgrund: WHO uppskattar att följsamheten till antidepressiva läkemedel är 40-70 procent, följsamheten är något högre till SSRI-preparatet. Försämrad följsamhet kan leda till allvarliga komplikationer och i värsta fall suicid. För att sjuk¬sköterskor ska kunna stödja patienter till förbättrad följsamhet behöver de kunskap om strategier som kan påverka följsamheten. Syfte: Syftet med litteratur-studien var att identifiera effekten av strategier som påverkar följsamheten vid behandlingen med SSRI-preparatet hos personer med depression och/eller ångest. Metod: Litteraturstudie består av tio artiklar med både kvalitativ och kvantitativ ansats. Artiklarna till den här studien har tagits från i CINAHL och PubMed. Resultat: Två huvudkategorier identifierades, Personcentrerad vård med fokusering på kunskap om SSRI-preparatet, vikten av en god vårdkontakt och tydlig information. Den andra huvudkategorin Interventioner uppmärksammade hur följsamheten kunde påverkas genom att ha regelbunden kontakt med vård-personal. Kategorierna presenterar olika strategier som kan påverka följsamheten med SSRI-behandlingen. Konklusion: Strategier som påverkar följsamheten till SSRI-preparatet har identifierats utifrån olika vårdprofessioner. Brister finns i hur strategier kan användas på lämpligast sätt för att behandlingen ska bli person-centrerad. Dock behövs mer forskning för att utveckla och förbättra strategierna som sjuksköterskor kan använda för att hjälpa patienter uppnå god effekt av SSRI-preparatet. / Background: WHO estimates that adherence to antidepressant medication is 40-70 percent, slightly higher for SSRIs. Non-adherence can lead to severe complications and in the worst case suicide. In order for nurses to better support patients, they need knowledge of strategies that can help improve patient adherence to their medical treatment. Aim: The aim of this literature study was to investigate the efficacy of strategies that affect adherence to the treatment with SSRI-medication for people with depression and/or anxiety. Method: The method involved a literature study consisting of ten articles some of which are qualitative and some of which are quantitative in approach. The articles for this study were found in CINAHL and PubMed. Findings: Two main categories were identified, Person-centered care with focus on knowledge of the SSRIs, the importance of a good healthcare relationship and patient information. The second main category, Interventions, focused on how adherence could be affected by having regular contact with healthcare professionals. The categories presented different strategies that can affect adherence to the SSRI-treatment. Conclusion: Strategies that affect adherence to SSRIs have been identified based on various professions. Strategies to make treatment more person-centred are required. More research is needed to develop and improve strategies that are useful for nurses to help patients achieve enhanced medication effect.

No description available.

<p>Individuals with mood disorders are particularly vulnerable to weight gain, due in part to an illness symptom profile that impacts appetite and energy and the iatrogenic weight-gain effects associated with psychotropic medications. The exact physiological mechanisms through which medication causes weight gain have yet to be clearly elucidated. The studies comprising this thesis examine changes in caloric consumption, physical activity and basal metabolic rate (BMR) in depressive disorder (MDD) patients starting on selective serotonin reuptake inhibitors (SSRIs). Since both depression and obesity have been linked to inflammation, we also monitored changes in cytokines and adipokines throughout treatment. In our sample, we observed a mean weight gain from baseline, prior to medication, to 6 months after the initiation of pharmacotherapy. We note that this weight gain is not likely due to increased caloric consumption, but could be related to the proportions of macronutrients being consumed and expended, as well as physical activity level. We also observed changes in adipokines and cytokines that are reflective of pharmacotherapy and not weight gain, even in the absence of clinical improvement. Collectively these studies have begun to shed light on the mechanisms involved in the weight gain experienced by MDD patients being treated with SSRI antidepressants. A better understanding of these mechanisms will lead to better management of the adverse metabolic side effects associated with psychotropic medication, and will improve patient compliance.</p> / Master of Science (MSc)

<p>Selective serotonin reuptake inhibitors (SSRIs) are the most common drugs prescribed to treat depression during pregnancy. The influence of SSRI exposure during pregnancy on fetus bone properties is not clearly understood. The overall objective of this thesis project was to investigate the short and long-term effects of <em>in utero</em> and postpartum exposure to SSRIs on bone in rats through measuring bone structural and material properties.</p> <p>Two studies with two types of SSRIs were carried out. Dams in the treated groups were randomly assigned to receive sertraline (10 mg/kg/day, N=5) in the first study and fluoxetine (10 mg/kg/day, N=17) in the second study. Control animals in the studies received saline in a flavoured gelatin vehicle. Rats were exposed to sertraline only during pregnancy, but fluoxetine was administered to the dams during pregnancy and also during breastfeeding. Rat offspring were sacrificed at 3, 7 and 26 weeks of age and left femurs and L6 vertebrae were analyzed for differences in morphology and mechanical properties.</p> <p>Maternal sertraline exposure resulted in significantly shorter femurs for the offspring at 3 weeks of age. Rat femurs from the sertraline group were also weaker at 3 and 7 weeks of age compared to controls. In comparison, <em>in utero</em> and postpartum exposure to fluoxetine did not have a negative impact on bone properties. In fact, the femurs from fluoxetine exposed offspring were significantly stronger at 3 weeks of age compared to the controls</p> <p>Findings in this project suggest that<strong> </strong>the type of SSRI used by pregnant woman should be considered as an important factor. Maternal sertraline exposure has a negative effect on offspring bone properties. Considering the fact that various mechanisms are involved in the influence of SSRIs on bone, further studies should be conducted to determine the mechanisms of this influence on bone properties <em>in utero </em>and through stages of development.<strong></strong></p> / Master of Applied Science (MASc)

Approximately 10% of pregnant women take antidepressants. Prenatal exposure to selective serotonin reuptake inhibitors (SSRIs), a class of antidepressants, has been shown to alter serotonergic signaling in the brain. However, the effects of SSRIs on peripheral serotonin (5HT) synthesis and/or signaling have largely been ignored. Serotonin in the gut is critical for intestinal function and dysregulation of this pathway is associated with intestinal disease. Therefore, the goal of this study was to determine the effects of perinatal exposure to the SSRI fluoxetine (Prozac®) on intestinal health in the offspring. Dams were given vehicle or fluoxetine hydrochloride (FLX 10 mg/kg/d; N=15) for 2 weeks prior to mating until weaning. We assessed markers of serotonergic signaling, inflammation, and composition of the gut microbiota in the offspring. Male offspring of fluoxetine-treated dams had significantly elevated serum levels of 5-HT and decreased expression of the 5HT2A receptor and MAO. In female offspring there was no effect of SSRI exposure to alter any components of serotonergic signaling. Although we did not find any evidence of increased inflammation following fluoxetine exposure, there were significant alterations in the composition of the gut microbiota in the exposed offspring. Male offspring of SSRIs-exposed mothers had changes in key components of the gut serotonergic system in association with elevated levels of serum 5-HT and alterations in the gut microbiota in adulthood. The impact of these changes on intestinal health and the reasons for the sex specific effects remain to be determined. / Thesis / Master of Science in Medical Sciences (MSMS)