Adverse Effects Of Fluoxetine Research Articles

Chronic fluoxetine treatment impairs motivation and reward learning by affecting neuronal plasticity in the central amygdala

To study the effects of chronic FLX treatment we combine an automated assessment of motivation and learning in mice with an investigation of various forms of neuronal plasticity in the central (CeA) and basolateral amygdala (BLA). We use immunohistochemistry to visualize neuronal types and perineuronal nets (PNN), and DI-staining to assess dendritic spine morphology. Gel zymography is used to test FLX's impact on matrix metalloproteinase-9 (MMP-9), an enzyme involved in synaptic plasticity. We show that chronic FLX treatment in non-stressed mice increases PNN-dependent plasticity in the BLA, while simultaneously impairing MMP-9-dependent plasticity in the CeA. Further, we illustrate how the latter contributes to anhedonia and deficits of reward learning. Behavioral impairments are accompanied by alterations in morphology of dendritic spines in the CeA towards a more immature state, most likely reflecting animals' inability to adapt. We strengthen the link between the adverse effects of FLX and its influence on MMP-9 by showing that behavior of MMP-9 knock-out animals remains unaffected by the drug. In conclusion, chronic FLX treatment differentially affects various forms of neuronal plasticity, which may explain its contradicting effects on the brain and behavior. Presented findings are of immediate clinical relevance since reported side effects of FLX pose a potential threat to patients.

Fluoxetine Inhibits Canonical Wnt Signaling to Impair Embryoid Body Morphogenesis: Potential Teratogenic Mechanisms of a Commonly Used Antidepressant.

Fluoxetine is one of the most commonly prescribed antidepressants in the selective serotonin reuptake inhibitor (SSRI) class. Epidemiologic studies have suggested a link between maternal fluoxetine use during pregnancy and an increased incidence of birth defects. However, the mechanisms by which fluoxetine adversely impacts embryonic developments are unknown. Here, we used the mouse P19C5 embryoid body (EB) as a 3D morphogenesis model to investigate the developmental toxicity of fluoxetine. Morphological and molecular changes in P19C5 EBs replicate the processes of axial elongation and patterning seen in early embryos, and these changes are specifically and sensitively altered by exposure to developmental toxicants. Treatment with fluoxetine, or its major metabolite, norfluoxetine, adversely affected EB morphogenesis at concentrations of 6 µM and above. Treatment with other serotonin reuptake inhibitors or serotonin itself did not impair EB morphogenesis, suggesting that the adverse effects of fluoxetine are independent of serotonin signaling. Gene expression analyses showed that various key developmental regulators were affected by fluoxetine, particularly those involved in mesodermal differentiation. Reporter assays demonstrated that fluoxetine inhibited canonical Wnt signaling, and that the pharmacologic activation of canonical Wnt signaling partially alleviated the morphogenetic effects of fluoxetine. Fluoxetine also exhibited cytostatic effects independently of inhibition of the serotonin transporter or canonical Wnt signaling. These results suggest that the SSRI-independent actions of fluoxetine, namely inhibition of canonical Wnt signaling and reduction of cellular proliferation, are largely responsible for the observed adverse morphogenetic impacts. This study provides mechanistic insight for further investigations on the teratogenicity of fluoxetine.

Effects of fluoxetine on behavior, antioxidant enzyme systems, and multixenobiotic resistance in the Asian clam Corbicula fluminea

Fluoxetine (FLX), a selective serotonin reuptake inhibitor, is widespread in aquatic environments. Despite its reported effects on behavior and reproduction in aquatic species, little is known about the effects of FLX on cellular detoxification and defense system in bivalves. Here, the adult Asian clam (Corbicula fluminea) was exposed to 0.5, 5, and 50μgL−1 FLX for 30d. Siphoning behavior was inhibited by treatment with 50μgL−1 FLX. Additionally, superoxide dismutase (SOD) activity in the gills and digestive glands significantly decreased (p<0.05) with 5 and 50μgL−1 FLX treatments, whereas catalase (CAT) activity and malondialdehyde (MDA) content markedly increased (p<0.05). Moreover, transcription of thioredoxin reductase (TR), glutathione peroxidase (GPx) and Glutathione S-transferase pi class (GSTpi) was significantly upregulated (p<0.05), whereas glutathione reductase (GR) was markedly downregulated (p<0.05). These findings suggest that FLX affects behavior and induces oxidative stress in C. fluminea. The downregulation of ATP-binding cassette (ABC) transportor genes (ABCB1, ABCC1 and ABCG2) transporter genes indicated that FLX might suppress the multixenobiotic resistance (MXR) system in C. fluminea. Our results provide new insights into the adverse effects of FLX on the cellular detoxification and MXR system of C. fluminea.

Classics in Chemical Neuroscience: Fluoxetine (Prozac)

Fluoxetine (Prozac) was the first major breakthrough for the treatment of depression since the introduction of tricyclic antidepressants (TCAs) and monoamine oxidase inhibitors (MAOIs) nearly 30 years earlier. It was the first selective serotonin reuptake inhibitor (SSRI) approved by the United States Food and Drug Administration, offering superior efficacy and reduced side effects relative to TCAs and MAOIs. Though a debate remains regarding the exact mechanism by which the clinical efficacy of fluoxetine is manifested, the importance of fluoxetine and related SSRIs to the field is unquestionable. The trade name Prozac has permeated popular culture, helping to raise awareness of depression and to diminish the prevalence of long-standing stigmas associated with this illness. In this Review, we will showcase the history and importance of fluoxetine to neuroscience in general, as well as for the treatment of depression, and review the synthesis, pharmacology, drug metabolism, and adverse effects of fluoxetine.

Serotonin and fluoxetine receptors are expressed in enamel organs and LS8 cells and modulate gene expression in LS8 cells

The selective serotonin re-uptake inhibitor (SSRI) fluoxetine is widely used in the treatment of depression in children and fertile women, but its effect on developing tissues has been sparsely investigated. The aim of this study was to investigate if enamel organs and ameloblast-derived cells express serotonin receptors that are affected by peripherally circulating serotonin or fluoxetine. Using RT-PCR and western blot analysis we found that enamel organs from 3-d-old mice and ameloblast-like cells (LS8 cells) express functional serotonin receptors, the rate-limiting enzyme in serotonin synthesis (Thp1), as well as the serotonin transporter (5HTT), indicating that enamel organs and ameloblasts are able to respond to serotonin and regulate serotonin availability. Fluoxetine and serotonin enhanced the alkaline phosphatase activity in the cell culture medium from cultured LS8 cells, whereas the expression of enamelin (Enam), amelogenin (Amel), and matrix metalloproteinase-20 (MMP-20) were all significantly down-regulated. The secretion of vascular endothelial growth factor (VEGF), monocyte chemotactic protein 1 (MCP-1), and interferon-inducible protein 10 (IP-10) was also reduced compared with controls. In conclusion, enamel organs and ameloblast-like cells express functional serotonin receptors. Reduced transcription of enamel proteins and secretion of vascular factors may indicate possible adverse effects of fluoxetine on amelogenesis.

Email Medication Counseling Services Provided by Finnish Community Pharmacies

The importance of email as a mode of communication between medication users and pharmacists is likely to increase. However, little is known about the email medication counseling practices of community pharmacies. To determine the prevalence of email medication counseling services in Finland and to assess the accuracy and comprehensiveness of responses by pharmacies providing the opportunity for email medication counseling to inquiries related to use of antidepressants. An inventory was made of all Finnish community pharmacies that provided the opportunity for email medication counseling. Data related to the accuracy and comprehensiveness of responses were collected, using a virtual pseudo-customer method with 3 scenarios related to common concerns of patients on antidepressants. Two inquiries were emailed to each pharmacy that provided the opportunity for email medication counseling in January and February 2005. The responses were content analyzed by 2 researchers, using a prestructured scoring system. Almost one-third (30%, n = 182) of Finnish community pharmacies maintained a working Web site, and 94% of those provided the opportunity for email medication counseling. An online "ask-the-pharmacist" service was offered by 13% (n = 23) of the pharmacies with a Web site. Pharmacies responded to 54% of the email inquiries sent by the virtual pseudo-customers. The response rate and the content score ratio between mean and maximum scores varied among the scenarios. The content score ratio was highest for the scenarios concerning the adverse effects of fluoxetine (0.53, n = 55) and interactions with mirtazapine (0.52, n = 63) and lowest for the scenario related to sexual dysfunction and weight gain associated with citalopram (0.38, n = 52). Community pharmacies are potential providers of email medication counseling services. However, more attention should be directed to responding to consumer inquiries and to the content of these responses.

Fluoxetine for Childhood Anxiety Disorders

The objective of this open study was to determine the efficacy and safety of fluoxetine for the treatment of children and adolescents with anxiety disorders. Twenty-one patients with overanxious disorders, social phobia, or separation anxiety disorder, who were unresponsive to previous psychopharmacological and psychotherapeutic interventions, were treated openly with fluoxetine for up to 10 months. Patients with lifetime histories of obsessive-compulsive disorder (OCD) or panic disorder, or with current major depression, were excluded. Beneficial and adverse effects of fluoxetine were ascertained using the improvement and severity subscales of the Clinical Global Impression Scale (CGIS) in two ways: (1) independent chart reviews by two child psychiatrists and (2) prospective assessments by the treating nurses and the patients' mothers. Eighty-one percent (n = 17) of patients showed moderate to marked improvement in anxiety symptoms. The severity of anxiety as measured by the CGIS was also significantly reduced from marked to mild (effect size: 2.3). There were no significant side effects. These results suggest that fluoxetine may be an effective and safe treatment for nondepressed children and adolescents with anxiety disorders other than OCD and panic disorder. Future investigations using double-blind, placebo-controlled methodologies are warranted.

In utero exposure to fluoxetine HCl increases hematoma frequency at birth

The present study was undertaken to determine if fluoxetine HCl (Prozac, Dista Products Ltd., Liverpool, UK) might cause adverse vascular effects, such as hematomas, in rats exposed in utero. Gravid Sprague-Dawley rats were administered 5.62 mg/kg fluoxetine HCl by oral gavage beginning on day 7 of gestation and ending the day of birth. A control group received distilled water by oral gavage during gestation. At birth, offspring of both groups were assessed for visible adverse vascular effects. Fluoxetine HCl-exposed offspring showed a statistically higher frequency of skin hematomas when compared to water controls. This result is consistent with known adverse effects of fluoxetine and lends support to a recently published report that attempted to link fluoxetine HCl use to bleeding episodes in eight patients being treated for obsessive-compulsive disorder. The results of this study suggest caution in the prolonged use of this medication during pregnancy and in patients with predisposing conditions that may increase the chances of bleeding.

Fluoxetineʼs spectrum of action in premenstrual syndrome

This study extends our previous report of the efficacy and tolerability of fluoxetine in severe premenstrual syndrome (PMS), describes which aspects of the disorder are responsive to such treatment, and assesses the relationship between steady-state drug level and clinical outcome. Twenty-one women with documented PMS satisfied criteria for late luteal phase dysphoric disorder (DSM-III-R) and accepted the offer of a double-blind, randomized crossover trial of fluoxetine hydrochloride 20 mg/day vs placebo. Symptom severity was measured with daily self-rating, monthly premenstrual assessment forms and psychiatric interviews after 3 months each of baseline, placebo and fluoxetine treatment. Compared with an inconsistent placebo response, fluoxetine produced marked improvement in 15 of 16 women completing the trial, eight showing virtually complete remission of PMS symptoms. Fluoxetine's efficacy extended over a range of affective, physical and behavioural symptoms; its superiority obtained whether it preceded or followed placebo. Three women withdrew due to adverse effects of fluoxetine, and 10 of 16 completing the trial reported at least one adverse effect of this agent. Compared with placebo, fluoxetine produced more (but usually transient) insomnia, sweating, gastrointestinal and menstrual disturbance. Plasma levels of fluoxetine and its active metabolite were not reliably associated with efficacy nor with side effects. Serotonergic agents appear to have considerable promise in treating a range of symptoms in women with severe PMS.

Adverse Effects of Fluoxetine

havior were more consistent than those seen with meth ylphen idate , which differs from placebo only at marginal levels (p = 0.056) at this stage of the study . As in other studies , fenfluramine caused drow­ siness in some children (although not severe in any case), and the differences approached significance both in comparison with placeb o (p = 0 .052) and meth ylphen idate (p = 0.052). We observed a non­ significant trend for fenfluramine to cause anorexia, but so far, this is less apparent than the differences between methylphenidate and placebo (p < 0.10 ). We have also a see n a nonsignificant tenden cy for less akathisia with fenflur amine than with placebo (p = 0 .06 8), which may be as a result of a mild anxiol ytic effect or may be secondary to the reduction in activity level. One heretofore unreported side effect is a very vivid report of a 7-year-old girl who developed a peculi ar body odor and halitosis that co incided exactly with the times of fen­ fluramine treatment. We observed no increases in insomnia, dizziness , or diarrhea with fenfluramine , although these are sometimes report ed to occ ur with the drug (Aman and Kern , 1989). We also looked at heart rate, blood pressu re, and body weight in these children. Analysi s of varian ce indic ated that all three cardio­ vascular measures were significantly affected by the medications . Fen­ fluramine was associ ated with reductions in eac h, but all sig nifica nt comparisons were with respect to methylphenidate , which tended to elevate heart rate and blood pressure . As in most studies, fenfluramin e produced significant weight losses in these children (p = 0. 01) . Our subjects lost about 1.8 pounds (0.8 2 kg) relative to their placebo weights during the 4 weeks the y received medic ation . Finally, two groups of sympt oms that do not appear on the DOTES Scale occurred fairly often in our sample. Seven of our subjects were reported to have difficulties wi th en uresis and encopresis, and another four demon strated stereotyp y and self-in jurious behavior. Enure sis and encopresis were lowest when the childre n were taking methylphen i­ date , appearing to worsen both with placebo (p = 0 .068) and fen­ fluramin e (p = 0 .068 ) . The emergence of these symptoms (usually in childr en who had previously been maintained on methylphenidate) has probably caused more distre ss than any other side effect in this study . Furthermore , it is a well-established fact that moderate-t o-high doses of psychostimul ants can induce stereotypic behavior in labora­ tory animal s (Randrup and Munkvad, 1974 ), and sterotypies may occur de novo (or existing stereo typies may be exacerbated) at lower doses of stimulants in children with developmental disabilities (A man, 1982). Both enure sis/encopresis and stereotypy/self-injury are obviousl y of rele vance to researchers and cli nicians working with de velopmentally delayed clinical popul ations. Other researchers working with devel­ opmentally delayed children may wish to add these symptoms to their inventory of side effec ts if they are using the DOTES to monitor side effects. Furthe rmore , if the DOTES is revi sed in the future , its de­ velopers should seriously consider add ing these and other relevant items to document such potential side effects .