Evidence suggests that selective serotonin reuptake inhibitors (SSRIs, a class of antidepressant medications) may contribute to increased breast cancer risk by stimulating the secretion of prolactin, a potential tumour promoter. The main objective of this study was to determine breast cancer risk associated with the duration, dosage and timing of SSRI use among women, with control for a limited set of confounders. This thesis project, conducted within the context of a population-based two-stage case-control study, consisted of a record linkage study utilizing three Saskatchewan health services databases. Cases included 1,273 women with primary breast cancer diagnosed between January 1, 2003 and December 31, 2005, and controls consisted of 12,730 subjects randomly selected from the province’s population registry. Data on SSRI use was compiled from the Saskatchewan prescription drug plan database. Information on a limited set of established risk factors for breast cancer that may confound this relationship was ascertained from the population registry and the prescription database. Cases and controls were similar in terms of age, total number of consecutive years eligible for prescription coverage and indicators of socioeconomic status. Compared to controls, cases were more likely to be married and to have used hormone therapy and/or oral contraceptives. Compared to nonusers, results indicated that the use of SSRIs for three or more years (as estimated by having filled 36 or more prescriptions for all SSRIs combined during the main exposure window more than two years prior to index date) was not associated with an increased risk of breast cancer (OR= 1.08, 95% CI: 0.74-1.58), controlling for age, marital status, oral contraceptive and hormone therapy use. In addition, no suggestion of increased risk was detected for long-term exposures to individual SSRIs (24 or more prescriptions filled during the main exposure window) and in relation to total combined SSRI use 2-7 years and more than seven years prior to index date. However, these risk estimates may have been affected by potential sources of information bias and confounding. In summary, these results do not provide evidence to suggest that the risk of breast cancer is increased with the use of SSRIs. / Thesis (Master, Community Health & Epidemiology) -- Queen's University, 2008-01-08 13:51:38.74

Fluoxetine, a selective serotonin re-uptake inhibitor (SSRI) and the active ingredient in Prozac®, is found in the environment and disrupts feeding and metabolism in exposed fish. The objective of this research was to investigate the mechanisms involved in the feeding and metabolism disruption in the model goldfish (Carassius auratus). Two short-term waterborne fluoxetine exposures (7- and 14-days) were performed using two environmentally relevant doses of fluoxetine (0.5 and 1 μg/L) and metabolic effects at the level of the brain, liver, serum and bile in goldfish were investigated. Abundances of mRNA transcripts coding for six feeding neuropeptides were examined to determine which may be involved in the initial neural changes associated with decreased appetite in goldfish. The 7-day fluoxetine exposure at 1 μg/L caused corticotropin-releasing factor (CRF) mRNA levels to increase by 2-fold in female hypothalamus and telencephalon, indicating that CRF may be one of the first of the feeding neuropeptides to be altered. Six hepatic miRNAs were also evaluated in the goldfish liver that were previously associated with fluoxetine exposure in zebrafish (Danio rerio). Following the 7-day exposure at 1 μg/L, miR-22b, miR-140, miR-210, miR-301a and miR-457b levels increased in the female goldfish liver by 4-6 fold. The 14-day fluoxetine exposure at 1 μg/L caused 2-fold increases in miR-210, miR-301a, miR-457b and let-7d in male goldfish liver. These miRNAs were associated with the down-regulation of anabolic metabolic pathways in zebrafish, indicating a conservation of miRNA and fluoxetine effect between fish species. Serum and bile metabolite profiles of fluoxetine exposed goldfish were evaluated using ultra performance liquid chromatography coupled to quadrupole time of flight mass spectrometry. Following the 14-day exposure at 1 μg/L, the bile metabolite profiles of male goldfish were significantly different from controls as detected by cluster analysis and fluoxetine was tentatively identified in the serum. No other discriminant metabolites were identified as of yet. The data presented suggest that fluoxetine causes metabolic disruption in goldfish at multiple organ levels. Because of the widespread detection of fluoxetine and other emerging SSRIs in the aquatic environment, future research is required to firmly establish this pharmaceutical class as a metabolic and endocrine disrupting chemical.

Animal personality can be defined as a set of physiological and behavioral characteristics that differ between individuals, but are consistent over time and across situations. The evolution of individual differences in behavior that are consistent over time and situations is still not clear. Our understanding of why animals have personality can be improved by investigating the underlying physiological mechanisms of animal behavior. Serotonin is a key monoamine that serves as a physiological modulator of animal behavior. Selective serotonin reuptake inhibitors are a group of chemicals that increase levels of serotonin in the brain. Fluoxetine is one such chemical and is used to treat depression in humans. In the field cricket (Gryllus bimaculatus), increased levels of serotonin have been linked to higher activity and boldness, which are both personality traits. In the current study, the effects of induced serotonin on activity, exploration, boldness and aggression was investigated. My results show that injecting fluoxetine causes substantial changes in behavioral traits used to describe personality in field crickets. This result is opposite to previous studies, as serotonin induced individuals were less active, less explorative, and won less fights, compared to control individuals. This could be due to serotonin existing naturally within the circulatory system of the field cricket, whereas fluoxetine is a manufactured chemical intended for human receptors, or that fluoxetine has a similar effect in modulating personality in field crickets as in humans. Since fluoxetine acts similarly in field crickets as in humans, an increased understanding of the effects of induced serotonin on different behaviors in field crickets could be beneficial for treating psychological illnesses.

Depression is a common neuropsychiatric illness with a lifetime prevalence of 17% in the United States. The disease can severely impact the daily living and quality of life in patients. The monoamine hypothesis of depression implicates the neurotransmitter serotonin as mediating the pathophysiology. Selective serotonin reuptake inhibitors (SSRIs), a popular and efficacious class of antidepressants, increase serotonin concentrations in the brain. However, full clinical benefit may not be obtained for four to six weeks. This period of waiting for SSRIs to work becomes quite daunting for patients. Research has focused on delineating the control mechanisms surrounding the dorsal raphé nucleus (DRN), the serotonergic control center located in the midbrain. Much evidence points to changes in several receptor systems as the underlying cause of the delay. One particular serotonin receptor, 5-HT 1A , has been established to play a role in affecting the time course of clinical effect. We have targeted another receptor as a possible contributor to the delay: the stimulatory 5-HT 2A heteroreceptors located on GABAergic interneurons of the DRN. The 5-HT 2A receptors of the GABAergic interneurons receive stimulatory input from serotonergic collaterals branching off the DRN serotonergic neurons. The resultant stimulation causes GABA release and inhibition of the serotonergic neurons via GABA A receptors of the DRN, completing a feedback loop. We hypothesize that the 5-HT 2A receptors desensitize under constant stimulation, as in the case with SSRI administration, and as a result contribute to the time delay in the onset of action of SSRIs. Using the microdialysis technique, various receptor agonists and antagonists were administered to examine receptor changes and its influence on serotonin release in male Wistar rats. Our results demonstrate that GABA A receptors exert a large inhibitory influence on serotonergic neurotransmission. Local GABA release results from 5-HT 2A receptor stimulation. Furthermore, serotonin appears to trend back towards basal levels, suggesting a possible desensitization process occurring under constant agonism of 5-HT 2A receptors. The development of our pharmacodynamic model quantitatively shows a slow desensitization process, which may also contribute to the time delay observed with the onset of action of SSRIs.

Panic disorder (PD) is a debilitating anxiety disorder that often reduces the quality of life and some of its symptoms are physical distress and fear. PD is often comorbid with other anxiety disorders and depressive disorders and also cardiovascular and respiratory illnesses. Pharmacotherapy and psychotherapy are the two most common treatment options for people with PD. A standard type of pharmacotherapy is selective serotonin reuptake inhibitors (SSRI) which in short work by increasing the level of serotonin in the brain and has been shown to be efficacious and safe. A vital brain structure that is closely linked to PD is the amygdala, and some of its functions are learning, emotional processing, and memory. There seems to be a functional and structural abnormality in the amygdala for people with PD compared to healthy individuals, for example, a smaller volume of gray matter and increased activity. The aim of the thesis is to conduct a systematic review on the effect of SSRIs on the functional alterations of the amygdala in patients suffering from PD. The present systematic review will try to answer the question: If SSRIs affect amygdala activation for PD patients compared to healthy individuals who are currently not undergoing any kind of pharmacotherapy. The results showed opposite findings; one study did not detect activation changes in the amygdala for PD patients using SSRIs, one detected higher activity in the right amygdala, whereas the other two showed a decrease in the left amygdala (one study did not specify left, bilateral, or right). More research regarding amygdala activation in PD patients using SSRIs is needed due to the small scale of studies currently available.

No description available.

10-15% of women take antidepressants during pregnancy. Selective serotonin reuptake inhibitors (SSRIs) are most commonly used for perinatal depression. Perinatal exposure to SSRIs has been shown to disrupt the development of serotonergic signaling pathways in the central nervous system (CNS); however, the effects on the developing enteric nervous system (ENS) remain relatively unexplored. We hypothesized that early life exposure to SSRIs would influence the structural development of the gastrointestinal (GI) tract. We further hypothesized that these structural changes could lead to clinically relevant functional outcomes, such as modifications in susceptibility to inflammation and altered GI motility. Female Wistar rats were given the SSRI, fluoxetine, or vehicle from 2 weeks prior to mating through gestation until weaning. At postnatal day 1 (P1), postnatal day 21 (P21; weaning) and 6 months of age (P6 months) intestines were harvested to assess for structural changes. At P6M, intestines were collected to assess motility in vitro and subsets of the offspring were treated with dextran sulfate sodium (DSS) to assess susceptibility to colitis. At P1, there was a significant decrease in serotonergic neurons in the female colon. At P21, there was a significant increase in serotonergic neurons of both sexes in the colon. At P6M, there was a significant increase in the frequency and velocity of long-distance contractions in the colon when both sexes were combined and an increase in ZO-1 in male colon. In conclusion, SSRI exposure in utero appears to have structural and functional consequences on the developing ENS in the SSRI exposed offspring. The structural consequences are seen in both sexes at P21 and although the structural changes to the ENS resolve by 6 months, motility in the colon continues to be significantly altered. There were no significant differences in chemical colitis, however, we did see difference of quantitative mRNA cytokines, chemokines and extracellular matrix components which may suggest differences in mucosal immune response. The mechanisms by which these changes occur remain to be explored. / Thesis / Master of Science (MSc)

Selective Serotonin Reuptake Inhibitors (SSRIs) are the most frequently prescribed class of drugs worldwide and are implemented in the treatment of depression and other psychiatric disorders. SSRIs relieve depressive symptoms by modulating levels of the neurotransmitter serotonin in the brain. SSRIs block the function of the serotonin transporter, thereby increasing concentrations of extracellular serotonin. However, serotonin levels in the neurons of the brain only account for 5% while the remaining 95% is present outside the brain. Serotonin receptors and transporter are located on bone resident cells (mesenchymal stem cells (MSCs)), osteoblasts and osteoclasts, and serotonergic activity is believed to affect bone homeostasis. Consequently, alterations in serotonin levels by SSRI treatment have the potential to alter bone formation and remodeling. Clinical reports correlate increase risk of bone fractures and delayed bone healing with SSRI use. Metallic implants are commonly used as orthopedic and dental implants to fix bony defects. Surface modifications have been used to increase the level of bone to implant contact by controlling the differentiation of MSCs into an osteoblastic linage and facilitate bone production. However, it is not known if SSRIs can affect MSCs osteoblastic differentiation and bone remodeling signaling in response to microstructured biomaterials. The aims of this study were: 1) Investigate the effects of SSRIs on MSCs differentiation on microstructured titanium (Ti), 2) Determine the effects of SSRIs on bone remodeling signaling and osteoclast activation, and 3) Elucidate the effects of SSRIs on serotonin receptors and their effect on bone remodeling. To investigate this, human MSCs were grown on tissue culture polystyrene (TCPS), smooth Ti (PT) or microstructured Ti (SLA) surfaces under exposure to therapeutic concentrations of commonly prescribed antidepressants (SSRIs (fluoxetine, sertraline, paroxetine), Selective Norepinephrine Reuptake Inhibitor (SNRI) (duloxetine) and other regularly prescribed antidepressants (bupropion)) during differentiation toward osteoblasts. Osteoblastic differentiation was assessed in MSCs after treatment with the drugs (0.1μM, 1μM, 10μM) by alkaline phosphatase activity and osteocalcin levels. Antidepressant treatment decreased levels of MSC differentiation markers on microstructured Ti surfaces. Furthermore, treatment dose-dependently decreased protein levels secreted by MSCs which are important for bone formation (BMP2, VEGF, Osteoprotegerin), and increased those involved in bone resorption (RANKL). To determine the effect of SSRIs on bone remodeling signaling and osteoclast activation, human osteoclasts were either directly exposed to antidepressants or conditioned media obtained from MSCs treated with antidepressants on Ti surfaces, after which, enzymatic tartrate-resistant acid phosphatase (TRAP) activity was assessed. Antidepressants increased TRAP activity both directly and through treated MSCs, with the highest levels evident after treatment with conditioned media from MSCs on microstructured Ti surfaces. To elucidate the effects of serotonin receptors and their effect on bone remodeling, receptors were pharmacologically inhibited. Surface roughness decreased gene expression of HTR2A, HTR1B, and HTR2B, and antidepressant treatment increased their expression. Inhibition of HTR2A decreased RANKL protein levels, while inhibition of other serotonin receptors had no effect on RANKL or OPG levels. These studies suggest that antidepressants inhibit MSCs differentiation on microstructured Ti surfaces and increase levels of proteins associated with bone resorption. Additionally, our results showed that RANKL is regulated by serotonin receptor HTR2A. Taken together, our results suggest that antidepressants have a negative effect on osteoblastic differentiation, compromising bone formation and enhancing bone resorption, which can be detrimental to patients under orthopedic and dental treatment.

Vendula Dvořáčková Attitudes of patients toward antidepressant medication Master's thesis Charles University in Prague, the Faculty of Pharmacy in Hradec Králové Department of Biological and Medical Sciences Pharmacy Background: The master's thesis deals with evaluation of attitudes of inpatients in the psychiatric clinic of Military University Hospital Prague. The main task was to clarify the relation between therapy attitude and the prescribed medication, diagnosis and sociodemographic characteristics. Methods: The data were collected using the Drug Attitude Inventory questionnaire (Czech version by Masopust) where sum of negative and positive answers was used to determine the patient's general attitude. Patients' characteristics were acquired from a data-entry form, specific medication from the medical records. Results: In the observed group women seemed to have a more positive attitude toward the treatment compared to men, similarly to people with a higher level of education and patients between 31 - 40 years of age in comparison with other age groups. The most positive responses were observed in patients who were prescribed agomelatine, trazodone and paroxetine. People diagnosed with personal disorders or affective bipolar disorder inclined to positive answers as well, on the other hand most negative...

Selective Serotonin Reuptake Inhibitors and Bone mineral Density in a Population of U.S. Premenopausal Women May 2011 M.S., UNIVERSITY of Massachusetts Amherst Directed by: Professor Elizabeth R. Bertone-Johnson Low bone mineral density (BMD) in post-menopausal women is a risk factor for bone fractures and osteoporosis development. Prior studies in post-menopausal women have shown the use of antidepressant medications, specifically selective serotonin reuptake inhibitors (SSRIs) to be inversely related to BMD. However, the association has not been studied in pre-menopausal women. Current SSRI use is widespread with 8% of U.S. women age 18-44 reporting use. We evaluated the association between SSRIs and BMD and bone mineral content (BMC) cross-sectionally using data from the University of Massachusetts Vitamin D Status Study. SSRI use, diet, and lifestyle factors were assessed by questionnaire. BMD and BMC were measured using dual-energy x-ray absorptiometry (DEXA). The study included 256 women aged 18-30 (mean=21.6 years, SD=4.3 years). In this population, SSRI use was 5%, BMD values ranged from 0.97-1.38 g/cm2 (mean 1.16, SD 0.08), and BMC values ranged from 1833g to 3682g (mean 2541.5, SD=349.2). After adjustment for age, body mass index, and physical activity, mean BMD in the 13 users of SSRIs was 1.15g/cm2 (SD=0.06) compared to 1.16g/cm2 (SD=0.77) in the 243 non-users (p =0.66). After the same adjustments, mean BMC in the 13 users was 2467.1g (SD=285.0) compared to 2547.6g (SD=352.6) in the 243 non-users (p=0.94). Our findings do not support an inverse association between SSRI use and BMD or BMC. However, given the prevalence of SSRI use in young women and the potential for adverse effects on bone health, further study of this association is warranted.