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Acute Fluoxetine Treatment Induces Slow Rolling of Leukocytes on Endothelium in Mice

PubMed Central

Herr, Nadine; Mauler, Maximilian; Witsch, Thilo; Stallmann, Daniela; Schmitt, Stefanie; Mezger, Julius; Bode, Christoph; Duerschmied, Daniel

2014-01-01

Objective Activated platelets release serotonin at sites of inflammation where it acts as inflammatory mediator and enhances recruitment of neutrophils. Chronic treatment with selective serotonin reuptake inhibitors (SSRI) depletes the serotonin storage pool in platelets, leading to reduced leukocyte recruitment in murine experiments. Here, we examined the direct and acute effects of SSRI on leukocyte recruitment in murine peritonitis. Methods C57Bl/6 and Tph1−/− (Tryptophan hydroxylase1) mice underwent acute treatment with the SSRI fluoxetine or vehicle. Serotonin concentrations were measured by ELISA. Leukocyte rolling and adhesion on endothelium was analyzed by intravital microscopy in mesentery venules with and without lipopolysaccharide challenge. Leukocyte extravasation in sterile peritonitis was measured by flow cytometry of abdominal lavage fluid. Results Plasma serotonin levels were elevated 2 hours after fluoxetine treatment (0.70±0.1 µg/ml versus 0.27±0.1, p = 0.03, n = 14), while serum serotonin did not change. Without further stimulation, acute fluoxetine treatment increased the number of rolling leukocytes (63±8 versus 165±17/0.04 mm2min−1) and decreased their velocity (61±6 versus 28±1 µm/s, both p<0.0001, n = 10). In Tph1−/− mice leukocyte rolling was not significantly influenced by acute fluoxetine treatment. Stimulation with lipopolysaccharide decreased rolling velocity and induced leukocyte adhesion, which was enhanced after fluoxetine pretreatment (27±3 versus 36±2/0.04 mm2, p = 0.008, n = 10). Leukocyte extravasation in sterile peritonitis, however, was not affected by acute fluoxetine treatment. Conclusions Acute fluoxetine treatment increased plasma serotonin concentrations and promoted leukocyte-endothelial interactions in-vivo, suggesting that serotonin is a promoter of acute inflammation. E-selectin was upregulated on endothelial cells in the presence of serotonin, possibly explaining the observed
Effects of in vitro, acute and chronic treatment with fluoxetine on the sympathetic neurotransmission of rat vas deferens.

PubMed

Pedroso, Shaista Poppe; de Souza, Bruno Palmieri; Jurkiewicz, Aron; Juriewicz, Neide H; da Silva Junior, Edilson Dantas

2017-03-01

It is described that fluoxetine treatment is able to induce ejaculatory disorders. However, the exact mechanism is still not fully understood. Therefore, this study was carried out to further evaluate the anti-ejaculatory effects of fluoxetine, using different approaches (in vitro or in vivo treatments), on the sympathetic neurotransmission of the rat vas deferens. Vas deferens from male Wistar rats were used to check the in vitro effects of fluoxetine 10 -6 M, 3.10 -6 M or 10 -5 M. Animals were also acutely (20mg/kg, i.p. 4h or 24h) or chronically (10mg/kg, i.p., 30days) treated with fluoxetine or drug-free vehicle. The vas deferens from non-treated and treated animals were isolated and mounted in an isolated organ bath for the study of the contractions induced by adrenergic agonists, tyramine, 5-HT, Ca 2+ or electrical field stimulation. In vitro or acute treatment with fluoxetine decreased the contraction induced by agonists, Ca 2+ or electrical field stimulation. The chronic treatment with fluoxetine decreased the contractions induced agonists, tyramine or Ca 2+ , but did not modify the contractions induced by electrical field stimulation. We have shown that in vitro or in vivo fluoxetine treatment is able to alter the sympathetic neurotransmission of the rat vas deferens which could be related to alterations in the calcium signalling. Copyright © 2016 Elsevier B.V. All rights reserved.
Effects of acute or repeated paroxetine and fluoxetine treatment on affective behavior in male and female adolescent rats

PubMed Central

Amodeo, Leslie R.; Greenfield, Venuz Y.; Humphrey, Danielle E.; Varela, Veronica; Pipkin, Joseph A.; Eaton, Shannon E.; Johnson, Jelesa D.; Plant, Christopher P.; Harmony, Zachary R.; Wang, Li; Crawford, Cynthia A.

2015-01-01

Rationale The SSRI antidepressant fluoxetine is one of the few drugs that is effective at treating depression in adolescent humans. In contrast, the SSRI paroxetine has limited efficacy and is more at risk for inducing suicidal behavior. Objective The purpose of the present study was to more fully characterize the differential actions of paroxetine and fluoxetine. Methods In Experiment 1, male and female rats were injected with paroxetine (2.5 or 10 mg/kg), fluoxetine (10 mg/kg), or vehicle for 10 days starting on postnatal day (PD) 35, and affective behaviors were assessed using sucrose preference and elevated plus maze tasks. A separate set of rats were used to examine monoamine levels. In Experiment 2, rats were injected with paroxetine (2.5, 5 or 10 mg/kg), fluoxetine (5, 10 or 20 mg/kg), or vehicle during the same time frame as Experiment 1 and anxiety-like behaviors were measured using elevated plus maze, light/dark box, and acoustic startle. Results Repeated SSRI treatment failed to alter sucrose preference, although both paroxetine and fluoxetine reduced time spent in the open arms of the elevated plus maze and light compartment of the light/dark box. Paroxetine, but not fluoxetine, enhanced acoustic startle and interfered with habituation. Serotonin turnover was decreased by both acute and repeated fluoxetine treatment but unaltered by paroxetine administration. Discussion These results show that repeated treatment with paroxetine and fluoxetine has dissociable actions in adolescent rats. In particular, paroxetine, but not fluoxetine, increases acoustic startle at low doses and may increase sensitivity to environmental stressors. PMID:26141193
Effects of acute or repeated paroxetine and fluoxetine treatment on affective behavior in male and female adolescent rats.

PubMed

Amodeo, Leslie R; Greenfield, Venuz Y; Humphrey, Danielle E; Varela, Veronica; Pipkin, Joseph A; Eaton, Shannon E; Johnson, Jelesa D; Plant, Christopher P; Harmony, Zachary R; Wang, Li; Crawford, Cynthia A

2015-10-01

The SSRI antidepressant fluoxetine is one of the few drugs that is effective at treating depression in adolescent humans. In contrast, the SSRI paroxetine has limited efficacy and is more at risk for inducing suicidal behavior. The purpose of the present study was to more fully characterize the differential actions of paroxetine and fluoxetine. In experiment 1, male and female rats were injected with paroxetine (2.5 or 10 mg/kg), fluoxetine (10 mg/kg), or vehicle for 10 days starting on postnatal day (PD) 35, and affective behaviors were assessed using sucrose preference and elevated plus maze tasks. A separate set of rats were used to examine monoamine levels. In experiment 2, rats were injected with paroxetine (2.5, 5, or 10 mg/kg), fluoxetine (5, 10, or 20 mg/kg), or vehicle during the same time frame as experiment 1, and anxiety-like behaviors were measured using elevated plus maze, light/dark box, and acoustic startle. Repeated SSRI treatment failed to alter sucrose preference, although both paroxetine and fluoxetine reduced time spent in the open arms of the elevated plus maze and light compartment of the light/dark box. Paroxetine, but not fluoxetine, enhanced acoustic startle and interfered with habituation. Serotonin turnover was decreased by both acute and repeated fluoxetine treatment but unaltered by paroxetine administration. These results show that repeated treatment with paroxetine and fluoxetine has dissociable actions in adolescent rats. In particular, paroxetine, but not fluoxetine, increases acoustic startle at low doses and may increase sensitivity to environmental stressors.
Acute fluoxetine modulates emotional processing in young adult volunteers.

PubMed

Capitão, L P; Murphy, S E; Browning, M; Cowen, P J; Harmer, C J

2015-08-01

Fluoxetine is generally regarded as the first-line pharmacological treatment for young people, as it is believed to show a more favourable benefit:risk ratio than other antidepressants. However, the mechanisms through which fluoxetine influences symptoms in youth have been little investigated. This study examined whether acute administration of fluoxetine in a sample of young healthy adults altered the processing of affective information, including positive, sad and anger cues. A total of 35 male and female volunteers aged between 18 and 21 years old were randomized to receive a single 20 mg dose of fluoxetine or placebo. At 6 h after administration, participants completed a facial expression recognition task, an emotion-potentiated startle task, an attentional dot-probe task and the Rapid Serial Visual Presentation. Subjective ratings of mood, anxiety and side effects were also taken pre- and post-fluoxetine/placebo administration. Relative to placebo-treated participants, participants receiving fluoxetine were less accurate at identifying anger and sadness and did not show the emotion-potentiated startle effect. There were no overall significant effects of fluoxetine on subjective ratings of mood. Fluoxetine can modulate emotional processing after a single dose in young adults. This pattern of effects suggests a potential cognitive mechanism for the greater benefit:risk ratio of fluoxetine in adolescent patients.
Intrauterine and lactation exposure to fluoxetine blunted in the offspring the aortic adaptive response induced by acute restraint stress.

PubMed

Marques, Bruno V D; Higashi, Carolina M; da S Novi, Daniella R B; Zanluqui, Nagela G; Gregório, Thais F; Pinge-Filho, Phileno; Gerardin, Daniela C C; Pelosi, Gislaine G; Moreira, Estefânia G; Ceravolo, Graziela S

2017-10-15

Selective serotonin reuptake inhibitors are the most widely prescribed antidepressants to women during pregnancy. Maternal treatment with fluoxetine can expose fetuses and neonates to higher levels of serotonin that plays a role in stress response. Thus, the aim of the study was to evaluate whether maternal treatment with fluoxetine interferes with aorta reactivity of adult male offspring after acute restraint stress. Wistar rats were gavaged with fluoxetine (5mg/kg/day) or water (control) during pregnancy and lactation. The experiments were performed in adult male offspring, treated or not with reserpine (4mg/Kg, ip, 28h before the experimental protocol). Fluoxetine and control rats were submitted to a single restraint stress session (ST) for 1h. Curves to phenylephrine were performed in thoracic aorta with endothelium. Aortic nitric oxide (NOx) were evaluated by the Griess method. The aortic contraction induced by phenylephrine was similar between control and fluoxetine rats. The acute stress reduced contraction in aorta of control ST compared to control, and L-NAME equaled this response. In fluoxetine rats, ST did not change the aortic constriction. Reserpine treatment restored the vasoconstriction in control ST, but did not interfere with aortic contraction in control, fluoxetine or fluoxetine ST. The NOx concentration was higher in aortas from control ST than control rats, and reserpine reduced NOx levels of control ST. The NOx concentration was similar between fluoxetine and fluoxetine ST rats, treated or not with reserpine. In conclusion, maternal treatment with fluoxetine blunted acute restraint stress-induced NO system activation and aortic adaptation in adult offspring. Copyright © 2017 Elsevier B.V. All rights reserved.
Contrasting effects of acute and chronic treatment with imipramine and fluoxetine on inhibitory avoidance and escape responses in mice exposed to the elevated T-maze.

PubMed

Gomes, Karina Santos; de Carvalho-Netto, Eduardo Ferreira; Monte, Kátia Cristina Da Silva; Acco, Bruno; Nogueira, Paulo José de Campos; Nunes-de-Souza, Ricardo Luiz

2009-03-30

The elevated T-maze (ETM) is an animal model of anxiety-like behavior that assesses two different defensive behavioral tasks in the same animal-acquisition of inhibitory avoidance and latency to escape from an open and elevated arm. In rats, cute and chronic treatments with anxiolytic-like drugs impair avoidance acquisition while only chronic administration of panicolytic-like drugs impairs open arm withdrawal. To date, only the acute effects of anxiolytic/anxiogenic or panicolytic/panicogenic drugs have been tested in the mouse ETM and the results have partially corroborated those found in the rat ETM. This study investigated the effects of acute (a single intraperitoneal injection 30 min before testing) and chronic (daily i.p. injections for 15 consecutive days) treatment with imipramine or fluoxetine, non-selective and selective serotonin reuptake inhibitors, respectively, on inhibitory avoidance and escape tasks in the mouse ETM. Neither acute nor chronic treatment with imipramine (0, 1, 5 or 10 mg/kg, i.p.) significantly changed the behavioral profile of mice in the two ETM tasks. Interestingly, while acute fluoxetine (0, 5, 10, 20 or 40 mg/kg, i.p.) facilitated inhibitory avoidance and impaired escape latency, chronic treatment (0, 5, 20 or 40 mg/kg, i.p.) with this selective serotonin reuptake inhibitor (SSRI) produced an opposite effect, i.e., it impaired inhibitory avoidance acquisition and facilitated open arm withdrawal. Importantly, acute or chronic treatment with imipramine (except at the highest dose that increased locomotion when given acutely) or fluoxetine failed to alter general locomotor activity in mice as assessed in an ETM in which all arms were enclosed by lateral walls (eETM). These results suggest that inhibitory avoidance acquisition is a useful task for the evaluation of acute and chronic effects of SSRI treatment on anxiety in mice. However, as open arm latency was actually increased and reduced by acute and chronic fluoxetine
Contribution of oxidative stress and prostanoids in endothelial dysfunction induced by chronic fluoxetine treatment.

PubMed

Simplicio, Janaina A; Resstel, Leonardo B; Tirapelli, Daniela P C; D'Orléans-Juste, Pedro; Tirapelli, Carlos R

2015-10-01

The effects of chronic fluoxetine treatment were investigated on blood pressure and on vascular reactivity in the isolated rat aorta. Male Wistar rats were treated with fluoxetine (10 mg/kg/day) for 21 days. Fluoxetine increased systolic blood pressure. Chronic, but not acute, fluoxetine treatment increased the contractile response induced by phenylephrine, serotonin (5-HT) and KCl in endothelium-intact rat aortas. L-NAME and ODQ did not alter the contraction induced by phenylephrine and 5-HT in aortic rings from fluoxetine-treated rats. Tiron, SC-560 and AH6809 reversed the increase in the contractile response to phenylephrine and 5-HT in aortas from fluoxetine-treated rats. Fluoxetine treatment increased superoxide anion generation (O2(-)) and the expression of cyclooxygenase (COX)-1 in the rat aorta. Reduced expression of nNOS, but not eNOS or iNOS was observed in animals treated with fluoxetine. Fluoxetine treatment increased prostaglandin (PG)F2α levels but did not affect thromboxane (TX)B2 levels in the rat aorta. Reduced hydrogen peroxide (H2O2) levels and increased catalase (CAT) activity were observed after treatment. The major new finding of our study is that chronic fluoxetine treatment induces endothelial dysfunction, which alters vascular responsiveness by a mechanism that involves increased oxidative stress and the generation of a COX-derived vasoconstrictor prostanoid (PGF2α). Moreover, our results evidenced a relation between the period of treatment with fluoxetine and the magnitude in the increment of blood pressure. Finally, our findings raise the possibility that fluoxetine treatment increases the risk for vascular injury, a response that could predisposes to cardiovascular diseases. Copyright © 2015 Elsevier Inc. All rights reserved.
Single fluoxetine treatment before but not after stress prevents stress-induced hippocampal long-term depression and spatial memory retrieval impairment in rats

PubMed Central

Han, Huili; Dai, Chunfang; Dong, Zhifang

2015-01-01

A growing body of evidence has shown that chronic treatment with fluoxetine, a widely prescribed medication for treatment of depression, can affect synaptic plasticity in the adult central nervous system. However, it is not well understood whether acute fluoxetine influences synaptic plasticity, especially on hippocampal CA1 long-term depression (LTD), and if so, whether it subsequently impacts hippocampal-dependent spatial memory. Here, we reported that LTD facilitated by elevated-platform stress in hippocampal slices was completely prevented by fluoxetine administration (10 mg/kg, i.p.) 30 min before stress. The LTD was not, however, significantly inhibited by fluoxetine administration immediately after stress. Similarly, fluoxetine incubation (10 μM) during electrophysiological recordings also displayed no influence on the stress-facilitated LTD. In addition, behavioral results showed that a single fluoxetine treatment 30 min before but not after acute stress fully reversed the impairment of spatial memory retrieval in the Morris water maze paradigm. Taken together, these results suggest that acute fluoxetine treatment only before, but not after stress, can prevent hippocampal CA1 LTD and spatial memory retrieval impairment caused by behavioral stress in adult animals. PMID:26218751
Sprague-Dawley and Fischer female rats differ in acute effects of fluoxetine on sexual behavior.

PubMed

Miryala, Chandra Suma J; Hiegel, Cindy; Uphouse, Lynda

2013-02-01

The selective serotonin reuptake inhibitor (SSRI), fluoxetine, leads to sexual dysfunction in a substantial proportion of women. In studies with the Fischer inbred rat, the 5-HT(1A) receptor has been implicated in this sexual dysfunction. Whether this association with 5-HT(1A) receptors holds for other rat strains is not known. The effects of acute fluoxetine on sexual behavior in two strains of rats that differ in their response to a 5-HT(1A) receptor agonist were examined. Whether the strain difference is comparable in naturally cycling and hormonally primed, ovariectomized rats was determined. Proestrous rats and ovariectomized rats, hormonally primed with estradiol benzoate and progesterone, were treated with varying doses of fluoxetine. Sexual behavior was examined before and after treatment with the SSRI. Lordosis to mount ratios, lordosis quality, and proceptive behaviors were quantified. Sprague-Dawley and Fischer females were compared on each of these measures. The IC(50) for inhibition of lordosis behavior was determined. In both the intact and the hormonally primed, ovariectomized model, Sprague-Dawley females were less sensitive to the effects of fluoxetine on sexual behavior. In both groups, fluoxetine showed dose dependency in behavioral inhibition, but a higher dose was required for Sprague-Dawley than for Fischer females. Naturally cycling, proestrous rats required a higher dose of fluoxetine than hormonally primed ovariectomized rats to produce significant inhibition of sexual behavior. Thus, the strain difference in the response to fluoxetine does not parallel strain differences in the response to a 5-HT(1A) receptor agonist. Acute treatment with fluoxetine inhibits lordosis behavior in both Fischer and Sprague-Dawley females and the strain difference cannot be explained by reported strain differences in the response to a 5-HT(1A) receptor agonist. Fluoxetine's inhibition of female rat sexual behavior may involve effects of the SSRI in addition to
Sprague-Dawley and Fischer Female Rats Differ in Acute Effects of Fluoxetine on Sexual Behavior

PubMed Central

Miryala, C.S.J.; Hiegel, C.; Uphouse, L.

2012-01-01

Introduction The selective serotonin reuptake inhibitor (SSRI), fluoxetine, leads to sexual dysfunction in a substantial proportion of women. In studies with the Fischer inbred rat, the 5-HT1A receptor has been implicated in this sexual dysfunction. Whether this association with 5-HT1A receptors holds for other rat strains is not known. Aim The effects of acute fluoxetine on sexual behavior in two strains of rats that differ in their response to a 5-HT1A receptor agonist were examined. Whether the strain difference is comparable in naturally cycling and hormonally primed, ovariectomized rats was determined. Main Outcome Measures Lordosis to mount ratios, lordosis quality, and proceptive behaviors were quantified. Sprague-Dawley and Fischer females were compared on each of these measures. The IC50 for inhibition of lordosis behavior was determined. Methods Proestrous rats and ovariectomized rats, hormonally primed with estradiol benzoate and progesterone, were treated with varying doses of fluoxetine. Sexual behavior was examined before and after treatment with the SSRI. Results In both the intact and the hormonally-primed, ovariectomized model, Sprague-Dawley females were less sensitive to the effects of fluoxetine on sexual behavior. In both groups, fluoxetine showed dose-dependency in behavioral inhibition, but a higher dose was required for Sprague-Dawley than for Fischer females. Naturally cycling, proestrous rats required a higher dose of fluoxetine than hormonally-primed ovariectomized rats to produce significant inhibition of sexual behavior. Thus, the strain difference in the response to fluoxetine does not parallel strain differences in the response to a 5-HT1A receptor agonist. Conclusions Acute treatment with fluoxetine inhibits lordosis behavior in both Fischer and Sprague-Dawley females and the strain difference cannot be explained by reported strain differences in the response to a 5-HT1A receptor agonist. Fluoxetine’s inhibition of female rat
Efficacy and safety of olanzapine/fluoxetine combination vs fluoxetine monotherapy following successful combination therapy of treatment-resistant major depressive disorder.

PubMed

Brunner, Elizabeth; Tohen, Mauricio; Osuntokun, Olawale; Landry, John; Thase, Michael E

2014-10-01

This study assessed prevention of relapse in patients with treatment-resistant depression (TRD) taking olanzapine/fluoxetine combination (OFC). Patients with major depressive disorder (MDD) who failed to satisfactorily respond to ≥ 2 different antidepressants for ≥ 6 weeks within the current MDD episode were acutely treated for 6-8 weeks, followed by stabilization (12 weeks) on OFC. Those who remained stable were randomized to OFC or fluoxetine for up to 27 weeks. Time-to-relapse was the primary efficacy outcome defined as 50% increase in Montgomery-Åsberg Depression Rating Scale score with Clinical Global Impressions-Severity of Depression score of ≥ 4; hospitalization for depression or suicidality; or discontinuation for lack of efficacy or worsening of depression or suicidality. A total of 444 patients were randomized 1:1 to OFC (N=221) or fluoxetine (N=223). Time-to-relapse was significantly longer in OFC-treated patients compared with fluoxetine-treated patients (p<0.001). Treatment-emergent weight gain and some mean and categorical fasting metabolic changes were significantly greater in OFC-treated patients. Clinically significant weight gain (≥ 7%) was observed in 55.7% of patients who remained on OFC throughout the study, including the relapse-prevention phase (up to 47 weeks). There were no significant differences between patients treated with OFC and fluoxetine in extrapyramidal symptoms or serious adverse events. We believe this is the first controlled relapse-prevention study in subjects with TRD that supports continued use of a second-generation antipsychotic beyond stabilization. A thorough assessment of benefits and risks (in particular metabolic changes) associated with continuing treatment with OFC or fluoxetine must be done based on individual patient needs.
Efficacy and Safety of Olanzapine/Fluoxetine Combination vs Fluoxetine Monotherapy Following Successful Combination Therapy of Treatment-Resistant Major Depressive Disorder

PubMed Central

Brunner, Elizabeth; Tohen, Mauricio; Osuntokun, Olawale; Landry, John; Thase, Michael E

2014-01-01

This study assessed prevention of relapse in patients with treatment-resistant depression (TRD) taking olanzapine/fluoxetine combination (OFC). Patients with major depressive disorder (MDD) who failed to satisfactorily respond to ⩾2 different antidepressants for ⩾6 weeks within the current MDD episode were acutely treated for 6–8 weeks, followed by stabilization (12 weeks) on OFC. Those who remained stable were randomized to OFC or fluoxetine for up to 27 weeks. Time-to-relapse was the primary efficacy outcome defined as 50% increase in Montgomery-Åsberg Depression Rating Scale score with Clinical Global Impressions−Severity of Depression score of ⩾4; hospitalization for depression or suicidality; or discontinuation for lack of efficacy or worsening of depression or suicidality. A total of 444 patients were randomized 1:1 to OFC (N=221) or fluoxetine (N=223). Time-to-relapse was significantly longer in OFC-treated patients compared with fluoxetine-treated patients (p<0.001). Treatment-emergent weight gain and some mean and categorical fasting metabolic changes were significantly greater in OFC-treated patients. Clinically significant weight gain (⩾7%) was observed in 55.7% of patients who remained on OFC throughout the study, including the relapse-prevention phase (up to 47 weeks). There were no significant differences between patients treated with OFC and fluoxetine in extrapyramidal symptoms or serious adverse events. We believe this is the first controlled relapse-prevention study in subjects with TRD that supports continued use of a second-generation antipsychotic beyond stabilization. A thorough assessment of benefits and risks (in particular metabolic changes) associated with continuing treatment with OFC or fluoxetine must be done based on individual patient needs. PMID:24801768
Chronic treatment with fluoxetine modulates vascular adrenergic responses by inhibition of pre- and post-synaptic mechanisms.

PubMed

Pereira, Camila A; Rodrigues, Fernanda L; Ruginsk, Silvia G; Zanotto, Camila Z; Rodrigues, José A; Duarte, Diego A; Costa-Neto, Claudio M; Resstel, Leonardo B; Carneiro, Fernando S; Tostes, Rita C

2017-04-05

Fluoxetine, a serotonin reuptake inhibitor (SSRI), has other effects in addition to blocking serotonin reuptake, including changes in the vasomotor tone. Whereas many studies focused on the acute effects of fluoxetine in the vasculature, its chronic effects are still limited. In the present study, we tested the hypothesis that chronic fluoxetine treatment modulates adrenergic vascular responses by interfering with post- and pre-synaptic mechanisms. Wistar rats were treated with vehicle (water) or chronic fluoxetine (10mg/kg/day) for 21 days. Blood pressure (BP) and heart rate were measured. Vascular reactivity was evaluated in perfused mesenteric arterial beds (MAB) and in mesenteric resistance arteries. Protein expression by western blot analysis or immunohistochemistry, β-arrestin recruitment by BRET and calcium influx by FLIPR assay. Fluoxetine treatment decreased phenylephrine (PE)-induced, but not electrical-field stimulation (EFS)-induced vasoconstriction. Fluoxetine-treated rats exhibited increased KCl-induced vasoconstriction, which was abolished by prazosin. Desipramine, an inhibitor of norepinephrine (NA) reuptake, increased EFS-induced vasoconstrictor response in vehicle-treated, but not in fluoxetine-treated rats. Chronic treatment did not alter vascular expression of α 1 adrenoceptor, phosphorylation of PKCα or ERK 1/2 and RhoA. On the other hand, vascular contractions to calcium (Ca 2+ ) as well as Ca 2+ influx in mesenteric arteries were increased, while intracellular Ca 2+ storage was decreased by the chronic treatment with fluoxetine. In vitro, fluoxetine decreased vascular contractions to PE, EFS and Ca 2+ , but did not change β-arrestin activity. In conclusion, chronic treatment with fluoxetine decreases sympathetic-mediated vascular responses by mechanisms that involve inhibition of NA release/reuptake and decreased Ca 2+ stores. Copyright © 2017 Elsevier B.V. All rights reserved.
Fluoxetine treatment ameliorates depression induced by perinatal arsenic exposure via a neurogenic mechanism

PubMed Central

Tyler, Christina R.; Solomon, Benjamin R.; Ulibarri, Adam L.; Allan, Andrea M.

2014-01-01

Several epidemiological studies have reported an association between arsenic exposure and increased rates of psychiatric disorders, including depression, in exposed populations. We have previously demonstrated that developmental exposure to low amounts of arsenic induces depression in adulthood along with several morphological and molecular aberrations, particularly associated with the hippocampus and the hypothalamic–pituitary–adrenal (HPA) axis. The extent and potential reversibility of this toxin-induced damage has not been characterized to date. In this study, we assessed the effects of fluoxetine, a selective serotonin reuptake inhibitor antidepressant, on adult animals exposed to arsenic during development. Perinatal arsenic exposure (PAE) induced depressive-like symptoms in a mild learned helplessness task and in the forced swim task after acute exposure to a predator odor (2,4,5-trimethylthiazoline, TMT). Chronic fluoxetine treatment prevented these behaviors in both tasks in arsenic-exposed animals and ameliorated arsenic-induced blunted stress responses, as measured by corticosterone (CORT) levels before and after TMT exposure. Morphologically, chronic fluoxetine treatment reversed deficits in adult hippocampal neurogenesis (AHN) after PAE, specifically differentiation and survival of neural progenitor cells. Protein expression of BDNF, CREB, the glucocorticoid receptor (GR), and HDAC2 was significantly increased in the dentate gyrus of arsenic animals after fluoxetine treatment. This study demonstrates that damage induced by perinatal arsenic exposure is reversible with chronic fluoxetine treatment resulting in restored resiliency to depression via a neurogenic mechanism. PMID:24952232
Sex-specific antidepressant effects of dietary creatine with and without sub-acute fluoxetine in rats

PubMed Central

Allen, Patricia J.; D'Anci, Kristen E.; Kanarek, Robin B.; Renshaw, Perry F.

2013-01-01

The potential role of metabolic impairments in the pathophysiology of depression is motivating researchers to evaluate the treatment efficacy of creatine, a naturally occurring energetic and neuroprotective compound found in brain and muscle tissues. Growing evidence is demonstrating the benefit of oral creatine supplements for reducing depressive symptoms in humans and animals. A novel question is whether dietary creatine, when combined with antidepressant drug therapy, would be more effective than either compound alone. To answer this question, four studies were conducted to investigate the behavioral effects of combined creatine and low-dose fluoxetine treatment using the forced swim test in male and female rats. Sprague-Dawley rats were fed powdered rodent chow supplemented with 0%, 2% or 4% w/w creatine monohydrate for 5 weeks. Rats were injected with fluoxetine (5.0 or 10.0 mg/kg) or saline according to a sub-acute dosing schedule. Female rats maintained on a 4% creatine diet displayed antidepressant-like effects compared to non-supplemented females prior to fluoxetine treatment. In contrast, creatine did not alter behavior reliably in males. Following drug treatment and a second forced swim trial, the antidepressant-like profile of creatine remained significant only in females co-administered 5.0 mg/kg fluoxetine. Moreover, in females only, supplementation with 4% creatine produced a more robust antidepressant-like behavioral profile compared to either dose of fluoxetine alone. Estrous cycle data indicated that ovarian hormones influenced the antidepressant-like effects of creatine. Addressing the issue of sex differences in response to treatment may affect our understanding of creatine, its relationship with depressive behavior, and may lead to sex-specific therapeutic strategies. PMID:22429992
Chronic fluoxetine treatment increases NO bioavailability and calcium-sensitive potassium channels activation in rat mesenteric resistance arteries.

PubMed

Pereira, Camila A; Ferreira, Nathanne S; Mestriner, Fabiola L; Antunes-Rodrigues, José; Evora, Paulo R B; Resstel, Leonardo B M; Carneiro, Fernando S; Tostes, Rita C

2015-10-15

Fluoxetine, a selective serotonin reuptake inhibitor (SSRI), has effects beyond its antidepressant properties, altering, e.g., mechanisms involved in blood pressure and vasomotor tone control. Although many studies have addressed the acute impact of fluoxetine on the cardiovascular system, there is a paucity of information on the chronic vascular effects of this SSRI. We tested the hypothesis that chronic fluoxetine treatment enhances the vascular reactivity to vasodilator stimuli by increasing nitric oxide (NO) signaling and activation of potassium (K+) channels. Wistar rats were divided into two groups: (I) vehicle (water for 21 days) or (II) chronic fluoxetine (10 mg/kg/day in the drinking water for 21 days). Fluoxetine treatment increased endothelium-dependent and independent vasorelaxation (analyzed by mesenteric resistance arteries reactivity) as well as constitutive NO synthase (NOS) activity, phosphorylation of eNOS at Serine1177 and NO production, determined by western blot and fluorescence. On the other hand, fluoxetine treatment did not alter vascular expression of neuronal and inducible NOS or guanylyl cyclase (GC). Arteries from fluoxetine-treated rats exhibited increased relaxation to pinacidil. Increased acetylcholine vasorelaxation was abolished by a calcium-activated K+ channel (KCa) blocker, but not by an inhibitor of KATP channels. On the other hand, vascular responses to Bay 41-2272 and 8-bromo-cGMP were similar between the groups. In conclusion, chronic fluoxetine treatment increases endothelium-dependent and independent relaxation of mesenteric resistance arteries by mechanisms that involve increased eNOS activity, NO generation, and KCa channels activation. These effects may contribute to the cardiovascular effects associated with chronic fluoxetine treatment. Copyright © 2015 Elsevier B.V. All rights reserved.
Early Prediction of Acute Antidepressant Treatment Response and Remission in Pediatric Major Depressive Disorder

ERIC Educational Resources Information Center

Tao, Rongrong; Emslie, Graham; Mayes, Taryn; Nakonezny, Paul; Kennard, Betsy; Hughes, Carroll

2009-01-01

The rate of symptom improvement during the early weeks of acute fluoxetine treatment is a good indicator of remission. This finding was made after evaluating the outcome of the fluoxetine treatment on 168 children and adults with depression.
A double-masked, placebo-controlled study of fluoxetine for hypochondriasis.

PubMed

Fallon, Brian A; Petkova, Eva; Skritskaya, Natalia; Sanchez-Lacay, Arturo; Schneier, Franklin; Vermes, Donna; Cheng, Jianfeng; Liebowitz, Michael R

2008-12-01

This study assessed the efficacy, durability, and tolerability of fluoxetine for hypochondriasis, a disorder for which controlled pharmacological trials are scarce. Fifty-seven patients with hypochondriasis were enrolled: 12 discontinued during the placebo run-in, and 45 were randomized to either fluoxetine or placebo for 12 weeks (acute treatment). Responder status was defined as a Clinical Global Impression rating for hypochondriasis of much or very much improved. Secondary outcome measures included severity of hypochondriasis, somatization, anxiety, and depression. Responders to acute treatment entered a 12-week maintenance phase to week 24. Sustained responders at week 24 entered a 12-week double-masked discontinuation phase. Primary analysis used the intent-to-treat sample. More patients responded with improvement in hypochondriasis when given fluoxetine compared with placebo, starting at week 8 (50.0% vs 19.0%, P = 0.03) and continuing to week 12 (62.5% vs 33.3%, P = 0.05). Mean dose at week 12 dose was 51.4 mg (SD, +/-23 mg). The acute treatment response was maintained to week 24 with more responders in the fluoxetine compared with the placebo group (54.2% vs 23.8%, P = 0.04). Significant improvement was not noted on the continuous secondary outcomes measures of hypochondriasis, with the exception of the Clinical Global Impression hypochondriasis severity scale at week 24. Likelihood of response was not associated with severity of psychiatric comorbidity. Durability of response after controlled drug discontinuation could not be reasonably assessed, given the small sample size of patients who entered the discontinuation phase (n = 10). Fluoxetine was well tolerated, with no significant differences in discontinuation due to side effects between treatment groups. Fluoxetine is a moderately effective and well-tolerated treatment for hypochondriasis.
Behavioral and neurogenomic transcriptome changes in wild-derived zebrafish with fluoxetine treatment

PubMed Central

2013-01-01

Background Stress and anxiety-related behaviors are seen in many organisms. Studies have shown that in humans and other animals, treatment with selective serotonin reuptake inhibitors (e.g. fluoxetine) can reduce anxiety and anxiety-related behaviors. The efficacies and side effects, however, can vary between individuals. Fluoxetine can modulate anxiety in a stereospecific manner or with equal efficacy regardless of stereoisomer depending on the mechanism of action (e.g. serotonergic or GABAergic effects). Zebrafish are an emerging and valuable translational model for understanding human health related issues such as anxiety. In this study we present data showing the behavioral and whole brain transcriptome changes with fluoxetine treatment in wild-derived zebrafish and suggest additional molecular mechanisms of this widely-prescribed drug. Results We used automated behavioral analyses to assess the effects of racemic and stereoisomeric fluoxetine on male wild-derived zebrafish. Both racemic and the individual isomers of fluoxetine reduced anxiety-related behaviors relative to controls and we did not observe stereospecific fluoxetine effects. Using RNA-sequencing of the whole brain, we identified 411 genes showing differential expression with racemic fluoxetine treatment. Several neuropeptides (neuropeptide Y, isotocin, urocortin 3, prolactin) showed consistent expression patterns with the alleviation of stress and anxiety when anxiety-related behavior was reduced with fluoxetine treatment. With gene ontology and KEGG pathway analyses, we identified lipid and amino acid metabolic processes, and steroid biosynthesis among other terms to be over-enriched. Conclusion Our results demonstrate that fluoxetine reduces anxiety-related behaviors in wild-derived zebrafish and alters their neurogenomic state. We identify two biological processes, lipid and amino acid metabolic synthesis that characterize differences in the fluoxetine treated fish. Fluoxetine may be acting on

Inhibitory effect of chronic oral treatment with fluoxetine on capsaicin-induced external carotid vasodilatation in anaesthetised dogs.

PubMed

Muñoz-Islas, Enriqueta; González-Hernández, Abimael; Lozano-Cuenca, Jair; Ramírez-Rosas, Martha Beatríz; Medina-Santillán, Roberto; Centurión, David; MaassenVanDenBrink, Antoinette; Villalón, Carlos M

2015-10-01

During migraine, capsaicin-sensitive trigeminal sensory nerves release calcitonin gene-related peptide (CGRP), resulting in cranial vasodilatation and central nociception. Moreover, 5-HT is involved in the pathophysiology of migraine and depression. Interestingly, some limited lines of evidence suggest that fluoxetine may be effective in migraine prophylaxis, but the underlying mechanisms are uncertain. Hence, this study investigated the canine external carotid vasodilator responses to capsaicin, α-CGRP and acetylcholine before and after acute and chronic oral treatment with fluoxetine. Forty-eight vagosympathectomised male mongrel dogs were prepared to measure blood pressure, heart rate and external carotid blood flow. The thyroid artery was cannulated for infusions of agonists. In 16 of these dogs, a spinal cannula was inserted (C1-C3) for infusions of 5-HT. The external carotid vasodilator responses to capsaicin, α-CGRP and acetylcholine remained unaffected after intracarotid or i.v. fluoxetine. In contrast, the vasodilator responses to capsaicin, but not those to α-CGRP or acetylcholine, were inhibited after chronic oral treatment with fluoxetine (300 µg/kg; for 90 days) or intrathecal 5-HT. Chronic oral fluoxetine inhibited capsaicin-induced external carotid vasodilatation, and this inhibition could partly explain its potential prophylactic antimigraine action. © International Headache Society 2015.
A comparative study of acute and subchronic effects of dothiepin, fluoxetine and placebo on psychomotor and actual driving performance.

PubMed Central

Ramaekers, J G; Muntjewerff, N D; O'Hanlon, J F

1995-01-01

1. The acute and subchronic effects of dothiepin 75-150 mg and fluoxetine 20 mg on critical fusion frequency (CFF), sustained attention and actual driving performance were compared with those of placebo in a double-blind, cross-over study involving 18 healthy volunteers. Drugs and placebo were administered for 22 days in evening doses. Fluoxetine doses were constant but dothiepin doses increased on the evening of day 8. Performance was assessed on days 1, 8 and 22 of each treatment series. Subjective sleep parameters and possible side effects were recorded on visual analogue scales on alternate treatment days. 2. Dothiepin reduced sustained attention on day 1 by 6.7% (95% confidence interval (C1): -12.0 to -1.3%) and CFF on day 22 by 1.1 (CI: -2.2 to -0.1) Hz. Fluoxetine reduced sustained attention days 1, 8 and 22 of treatment by 7.4, 6.7 and 6.5% respectively (CI: -11.3 to -3.6; -14.3 to -1.5 and -9.5 to -3.4). CFF decreased linearly over days during fluoxetine treatment and significantly differed from placebo on day 22 with 1.2 Hz (CI: -2.3 to -0.2). Neither drug significantly affected driving performance. Whilst receiving dothiepin, subjects complained of drowsiness on days 1-3 of treatment (mean rank 5.6; CI: 2.0 to 9.2) and slept 43 min longer (CI: 8.2 to 76.2).(ABSTRACT TRUNCATED AT 250 WORDS) PMID:7640146
Comparative efficacy, acceptability, and safety of medicinal, cognitive-behavioral therapy, and placebo treatments for acute major depressive disorder in children and adolescents: a multiple-treatments meta-analysis.

PubMed

Ma, Dongfeng; Zhang, Zhijun; Zhang, Xiangrong; Li, Lingjiang

2014-06-01

New generation antidepressant therapies, including serotonin-norepinephrine reuptake inhibitor (SNRIs) and selective serotonin reuptake inhibitors (SSRIs) were introduced in the late 1980s; however, few comprehensive studies compared the benefits and risks of various contemporary treatments for major depressive disorder (MDD) in pediatric patients. Multiple-treatments meta-analysis (MTM) was conducted to assess efficacy, acceptability, and safety of contemporary interventions in children and adolescents with MDD. Cochrane Library, AMED, CINAHL, EMBASE, LiLACS, MEDLINE, PSYCINFO, PSYNDEX, and Journal of Medicine and Pharmacy databases were searched for randomized controlled trials (RCTs) comparing medicinal interventions (citalopram, escitalopram, fluoxetine, mirtazapine, paroxetine, sertraline, venlafaxine), cognitive behavioral therapy (CBT), combined fluoxetine with CBT, and placebo treatment for acute MDD from January 1988 to March 2013. Treatment success, dropout rate, and suicidal ideation/attempt outcomes were measured. Bayesian methods were used to conduct a MTM including age and funding subgroups. A total of 21 RCTs (4969 participants) were identified. Combined fluoxetine/CBT exhibited the highest efficacy, with fluoxetine alone superior to CBT, paroxetine, sertraline, citalopram, escitalopram, and placebo treatment. Sertraline, paroxetine, escitalopram, and venlafaxine showed superior acceptability to fluoxetine and combined fluoxetine/CBT. Combined fluoxetine/CBT combination was less safe, though CBT was safer than fluoxetine alone. Combined fluoxetine/CBT, fluoxetine, and mirtazapine exhibited the highest efficacy; sertraline, escitalopram, venlafaxine, and paroxetine were the best tolerated; and mirtazapine and venlafaxine were the safest. Sertraline and mirtazapine exhibited optimally balanced efficacy, acceptability, and safety for first-line acute treatment of child and adolescent MDD.
Behavioral characterization of the alarm reaction and anxiolytic-like effect of acute treatment with fluoxetine in piauçu fish.

PubMed

Barbosa Júnior, Augusto; Alves, Fabiana Luca; Pereira, Aparecida de Sousa Fim; Ide, Liliam Midori; Hoffmann, Anette

2012-02-01

In Ostariophysan fish, the detection of the alarm substance liberated into the water as a consequence of an attack by a predator elicits an alarm reaction or anti-predatory behavior. In this study, experiments were performed to: (i) describe and quantitatively characterize the behavioral and ventilatory responses in piauçu fish (Leporinus macrocephalus), individually and as part of a school, to conspecific alarm substance (CAS) and; (ii) test the effect of acute fluoxetine treatment on alarm reaction. Histological analysis revealed the presence of club cells in the intermediate and superficial layers of the epidermis. The predominant behavioral response to CAS was freezing for fish held individually, characterized by the cessation of the swimming activity as the animal settles to a bottom corner of the aquarium. Fish exposed to CAS showed decrease in the mean ventilatory frequency (approximately 13%) relative to control. In schools, CAS elicited a biphasic response that was characterized by erratic movements followed by increased school cohesion and immobility, reflected as an increased school cohesion (65.5% vs. -5.8% for controls) and in the number of animals near the bottom of the aquarium (42.0% vs. 6.5% for controls). Animals treated with single i.p. injections of fluoxetine (10 μg/g b.w.) did not exhibit alarm behavior following CAS stimulation. These results show that an alarm pheromone system is present in piauçu fish, evidenced by the presence of epidermal club cells and an alarm reaction induced by CAS and consequently of a chemosensory system to transmit the appropriate information to neural structures responsible for initiating anti-predator behavioral responses. In addition, fluoxetine treatment caused an anxiolytic-like effect following CAS exposure. Thus, the alarm reaction in piauçu can be a useful model for neuroethological and pharmacological studies of anxiety-related states. Copyright © 2011 Elsevier Inc. All rights reserved.
Predictors and Moderators of Acute Outcome in the Treatment for Adolescents with Depression Study (TADS)

ERIC Educational Resources Information Center

Curry, John; Rohde, Paul; Simons, Anne; Silva, Susan; Vitiello, Benedetto; Kratochvil, Christopher; Reinecke, Mark; Feeny, Norah; Wells, Karen; Pathak, Sanjeev; Weller, Elizabeth; Rosenberg, David; Kennard, Betsy; Robins, Michele; Ginsburg, Golda; March, John

2006-01-01

Objective: To identify predictors and moderators of response to acute treatments among depressed adolescents (N = 439) randomly assigned to fluoxetine, cognitive-behavioral therapy (CBT), both fluoxetine and CBT, or clinical management with pill placebo in the Treatment for Adolescents With Depression Study (TADS). Method: Potential baseline…
Cognitive performance of juvenile monkeys after chronic fluoxetine treatment.

PubMed

Golub, Mari S; Hackett, Edward P; Hogrefe, Casey E; Leranth, Csaba; Elsworth, John D; Roth, Robert H

2017-08-01

Potential long term effects on brain development are a concern when drugs are used to treat depression and anxiety in childhood. In this study, male juvenile rhesus monkeys (three-four years of age) were dosed with fluoxetine or vehicle (N=16/group) for two years. Histomorphometric examination of cortical dendritic spines conducted after euthanasia at one year postdosing (N=8/group) suggested a trend toward greater dendritic spine synapse density in prefrontal cortex of the fluoxetine-treated monkeys. During dosing, subjects were trained for automated cognitive testing, and evaluated with a test of sustained attention. After dosing was discontinued, sustained attention, recognition memory and cognitive flexibility were evaluated. Sustained attention was affected by fluoxetine, both during and after dosing, as indexed by omission errors. Response accuracy was not affected by fluoxetine in post-dosing recognition memory and cognitive flexibility tests, but formerly fluoxetine-treated monkeys compared to vehicle controls had more missed trial initiations and choices during testing. Drug treatment also interacted with genetic and environmental variables: MAOA genotype (high- and low transcription rate polymorphisms) and testing location (upper or lower tier of cages). Altered development of top-down cortical regulation of effortful attention may be relevant to this pattern of cognitive test performance after juvenile fluoxetine treatment. Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.
Predictors of Treatment Response to Fluoxetine in PTSD Following a Recent History of War Zone Stress Exposure

DTIC Science & Technology

2010-07-01

routinely prescribed for acute stress disorder and early PTSD and recommended in the VA-DoD best practice guidelines, the efficacy of SSRIs as an early...selective serotonin reuptake inhibitors (SSRIs) are routinely prescribed for acute stress disorder and early PTSD and recommended in the VA-DoD best practice...1-0283 TITLE: Predictors of Treatment Response to Fluoxetine in PTSD Following a Recent History of War Zone Stress Exposure
Effects of ketamine and N-methyl-D-aspartate on fluoxetine-induced antidepressant-related behavior using the forced swimming test.

PubMed

Owolabi, Rotimi Adegbenga; Akanmu, Moses Atanda; Adeyemi, Oluwole Isaac

2014-04-30

This study investigated the effects of ketamine on fluoxetine-induced antidepressant behavior using the forced swimming test (FST) in mice. In order to understand the possible role of N-methyl-d-aspartate (NMDA) neurotransmission in the antidepressant effect of fluoxetine, different groups of mice (n=10) were administered with acute ketamine (3mg/kg, i.p.), acute NMDA (75mg/kg and 150mg/kg, i.p.) and a 21-day chronic ketamine (15mg/kg, i.p./day) were administered prior to the administration of fluoxetine (20mg/kg, i.p.) in the mice. Antidepressant related behavior (immobility score) was measured using the forced swimming test. The results showed that the acute ketamine and fluoxetine alone treatments elicited a significant (p<0.05) reduction in immobility score compared with saline control. Furthermore, pre-treatment with acute ketamine significantly enhanced by the fluoxetine-induced decrease in immobility score. In contrast, pre-treatment with NMDA (150mg/kg) significantly (p<0.05) reversed fluoxetine-induced decrease in immobility score. On the other hand, chronic administration of ketamine significantly elicited an increase in immobility score as well as reversed the reduction induced by fluoxetine. Similarly, NMDA administration at both 75mg/kg and 150mg/kg increased immobility score in chronically administered ketamine groups. Furthermore, chronic administration of ketamine, followed by NMDA (75mg/kg) and fluoxetine significantly elevated the immobility score when compared with the group that received NMDA and fluoxetine but not chronically treated with ketamine. It can be suggested) that facilitation of NMDA transmission blocked fluoxetine-induced reduction in immobility score, while down-regulation of NMDA transmission is associated with increase in fluoxetine-induced antidepressant-related behavior in mice. Down-regulation of the NMDA transmission is proposed as an essential component of mechanism of suppression of depression related behaviors by
Beneficial effect of fluoxetine treatment aganist psychological stress is mediated by increasing BDNF expression in selected brain areas

PubMed Central

Li, Gongying; Jing, Ping; Liu, Zhidong; Li, Zhiruo; Ma, Hongxia; Tu, Wenzhen; Zhang, Wei; Zhuo, Chuanjun

2017-01-01

SSRI antidepressant fluoxetine is widely used to treat psychological stress related disorders, however the underlying working mechanisms is not fully understood, as SSRIs can rapidly increase the extracellular serotonin levels but it normally takes weeks to reveal their therapeutic effect in the stress-related psychological disorders. Our previous study demonstrated that purely psychological stress without any physic stimuli induces a biphasic change in the expression of brain-derived neurotrophic factor (BDNF), which immediately decrease and then gradually increase after the stress; and that the latter BDNF increase in response to the psychological stress involves the activation of serotonin system. To investigate the role of BDNF in the fluoxetine treatment for stress-related psychological disorders, we examined the mRNA and protein levels of BDNF in the brain of Sprague-Dawley (SD) rats, which were pretreated with fluoxetine at 10 mg/kg or vehicle solution for 14 days, over 24 hour after an acute psychological stress exposure. In situ hybridization and immunohistochemistry were performed to detect the expression of BDNF at different time points in various brain regions after the psychological stress. We found that fluoxetine treatment completely blocked the BDNF decrease induced by the psychological stress, and also enhanced the gradual increase in the expression of BDNF in most of the brain regions except VTA after the psychological stress. The results suggest that the enhancement in BDNF levels induced by chronic fluoxetine treatment mediates the therapeutic effect against psychological stress. PMID:29050222
Moclobemide versus fluoxetine in the treatment of major depressive disorder in adults.

PubMed Central

Lapierre, Y D; Joffe, R; McKenna, K; Bland, R; Kennedy, S; Ingram, P; Reesal, R; Rickhi, B G; Beauclair, L; Chouinard, G; Annable, L

1997-01-01

The objective of the present study was to compare the safety and efficacy of moclobemide versus fluoxetine in adult patients with major depressive disorder. The design of the study was a multicenter, double-blind, comparative, and randomized trial. A 1- to 2-week single-blind placebo washout phase was followed by 6 weeks of double-blind treatment with moclobemide or fluoxetine. A total of 150 patients were enrolled in the study. There were 128 patients eligible to be randomized, with 66 patients receiving moclobemide and 62 patients receiving fluoxetine. At the termination of the study, patients in the moclobemide group were receiving a mean dose of 440 mg +/- 123 mg, while the mean dose in the fluoxetine group was 35 mg +/- 8 mg. No significant treatment differences were found for any of the efficacy parameters. Headache and nausea were the most frequently reported adverse events in both treatment groups. Headache and blurred vision were reported significantly more often (P < 0.05) in the fluoxetine group, whereas significantly more dry mouth was reported (P < 0.05) in the moclobemide group. These results provide supporting evidence of the comparable efficacy of moclobemide and fluoxetine and the better tolerability of moclobemide when used in the treatment of major depressive disorder. Images Figure 3 PMID:9074306
New insights into the acute actions from a high dosage of fluoxetine on neuronal and cardiac function: Drosophila, crayfish and rodent models.

PubMed

Majeed, Zana R; Ritter, Kyle; Robinson, Jonathan; Blümich, Sandra L E; Brailoiu, Eugen; Cooper, Robin L

2015-01-01

The commonly used mood altering drug fluoxetine (Prozac) in humans has a low occurrence in reports of harmful effects from overdose; however, individuals with altered metabolism of the drug and accidental overdose have led to critical conditions and even death. We addressed direct actions of high concentrations on synaptic transmission at neuromuscular junctions (NMJs), neural properties, and cardiac function unrelated to fluoxetine's action as a selective 5-HT reuptake inhibitor. There appears to be action in blocking action potentials in crayfish axons, enhanced occurrences of spontaneous synaptic vesicle fusion events in the presynaptic terminals at NMJs of both Drosophila and crayfish. In rodent neurons, cytoplasmic Ca(2+) rises by fluoxetine and is thapsigargin dependent. The Drosophila larval heart showed a dose dependent effect in cardiac arrest. Acute paralytic behavior in crayfish occurred at a systemic concentration of 2mM. A high percentage of death as well as slowed development occurred in Drosophila larvae consuming food containing 100μM fluoxetine. The release of Ca(2+) from the endoplasmic reticulum in neurons and the cardiac tissue as well as blockage of voltage-gated Na(+) channels in neurons could explain the effects on the whole animal as well as the isolated tissues. The use of various animal models in demonstrating the potential mechanisms for the toxic effects with high doses of fluoxetine maybe beneficial for acute treatments in humans. Future studies in determining how fluoxetine is internalized in cells and if there are subtle effects of these mentioned mechanisms presented with chronic therapeutic doses are of general interest. Copyright © 2015 Elsevier Inc. All rights reserved.
Acute administration of fluoxetine normalizes rapid eye movement sleep abnormality, but not depressive behaviors in olfactory bulbectomized rats.

PubMed

Wang, Yi-Qun; Tu, Zhi-Cai; Xu, Xing-Yuan; Li, Rui; Qu, Wei-Min; Urade, Yoshihiro; Huang, Zhi-Li

2012-01-01

In humans, depression is associated with altered rapid eye movement (REM) sleep. However, the exact nature of the relationship between depressive behaviors and sleep abnormalities is debated. In this study, bilateral olfactory bulbectomy (OBX) was carried out to create a model of depression in rats. The sleep-wake profiles were assayed using a cutting-edge sleep bioassay system, and depressive behaviors were evaluated by open field and forced swimming tests. The monoamine content and monoamine metabolite levels in the brain were determined by a HPLC-electrochemical detection system. OBX rats exhibited a significant increase in REM sleep, especially between 15:00 and 18:00 hours during the light period. Acute treatment with fluoxetine (10 mg/kg, i.p.) immediately abolished the OBX-induced increase in REM sleep, but hyperactivity in the open field test and the time spent immobile in the forced swimming test remained unchanged. Neurochemistry studies revealed that acute administration of fluoxetine increased serotonin (5-HT) levels in the hippocampus, thalamus, and midbrain and decreased levels of the 5-HT metabolite 5-hydroxyindoleacetic acid (5-HIAA). The ratio of 5-HIAA to 5-HT decreased in almost all regions of the brain. These results indicate that acute administration of fluoxetine can reduce the increase in REM sleep but does not change the depressive behaviors in OBX rats, suggesting that there was no causality between REM sleep abnormalities and depressive behaviors in OBX rats. © 2011 The Authors. Journal of Neurochemistry © 2011 International Society for Neurochemistry.
5-HT(1A) receptor antagonism reverses and prevents fluoxetine-induced sexual dysfunction in rats.

PubMed

Sukoff Rizzo, Stacey J; Pulicicchio, Claudine; Malberg, Jessica E; Andree, Terrance H; Stack, Gary P; Hughes, Zoë A; Schechter, Lee E; Rosenzweig-Lipson, Sharon

2009-09-01

Sexual dysfunction associated with antidepressant treatment continues to be a major compliance issue for antidepressant therapies. 5-HT(1A) antagonists have been suggested as beneficial adjunctive treatment in respect of antidepressant efficacy; however, the effects of 5-HT(1A) antagonism on antidepressant-induced side-effects has not been fully examined. The present study was conducted to evaluate the ability of acute or chronic treatment with 5-HT(1A) antagonists to alter chronic fluoxetine-induced impairments in sexual function. Chronic 14-d treatment with fluoxetine resulted in a marked reduction in the number of non-contact penile erections in sexually experienced male rats, relative to vehicle-treated controls. Acute administration of the 5-HT(1A) antagonist WAY-101405 resulted in a complete reversal of chronic fluoxetine-induced deficits on non-contact penile erections at doses that did not significantly alter baselines. Chronic co-administration of the 5-HT(1A) antagonists WAY-100635 or WAY-101405 with fluoxetine prevented fluoxetine-induced deficits in non-contact penile erections in sexually experienced male rats. Moreover, withdrawal of WAY-100635 from co-treatment with chonic fluoxetine, resulted in a time-dependent reinstatement of chronic fluoxetine-induced deficits in non-contact penile erections. Additionally, chronic administration of SSA-426, a molecule with dual activity as both a SSRI and 5-HT(1A) antagonist, did not produce deficits in non-contact penile erections at doses demonstrated to have antidepressant-like activity in the olfactory bulbectomy model. Taken together, these data suggest that 5-HT(1A) antagonist treatment may have utility for the management of SSRI-induced sexual dysfunction.
TREATMENT OF OBSESSIVE COMPULSIVE SYMPTOMS IN SCHIZOPHRENIA WITH FLUOXETINE

PubMed Central

Agarwal, Vivek; Agarwal, K.M.

2000-01-01

Obsessive compulsive symptoms have been reported to occur in high proportion in schizophrenia. Presence of obsessive compulsive symptoms in schizophrenia has poor prognostic significance. Because of the antiobsessional effect of the fluoxetine, present study was undertaken as preliminary investigation in cases of schizophrenia with obsessive compulsive symptoms. We conducted an open trial of 12 weeks duration in which fluoxetine was added up to 80 mg to the maintenance neuroleptic medication of outpatients of schizophrenia with obsessive compulsive symptoms diagnosed by DSM-IV criteria. Five patients showed a significant reduction in scores of Positive and Negative Syndrome Scale, Yale Brown Obsessive Compulsive Scale and Clinical Global Impression Scale. Two patients did not show any response. Fluoxetine was well tolerated by all the patients. The positive findings of this preliminary investigation supports the further investigations of fluoxetine as potential treatment in the obsessive compulsive symptoms in schizophrenia. PMID:21407959
Reduced efficacy of fluoxetine following MDMA ("Ecstasy")-induced serotonin loss in rats.

PubMed

Durkin, Sarah; Prendergast, Alison; Harkin, Andrew

2008-12-12

Long-term serotonin (5-HT) neuronal loss is currently a major cause of concern associated with recreational use of the substituted amphetamine 3,4 methylenedioxymethamphetamine (MDMA; "Ecstasy"). Such loss may be problematic considering that psychiatric disorders such as depression and anxiety and responses to first line treatments for these disorders are associated with 5-HT. In this study the effects of prior exposure to MDMA on behavioural and central neurochemical changes induced by the serotonin (5-HT) re-uptake inhibitor and antidepressant fluoxetine were examined in rats. Animals were administered MDMA (10 mg/kg. i.p.) four times daily for two consecutive days. One week later the animals were subjected to treatment with fluoxetine (10 mg/kg, i.p.). Fluoxetine treatment groups received either acute (saline injections for 20 days followed by 3 fluoxetine treatments over 24 h) or chronic (once daily fluoxetine for 21 days) drug administration. Prior exposure to MDMA resulted in an attenuation of fluoxetine-induced swimming behaviour in the modified forced swimming test (FST); a behavioural test of antidepressant action. In parallel MDMA treatment resulted in significant regional depletions of 5-HT and its metabolite 5-hydroxyindoleacetic acid (5-HIAA) accompanied by a reduction in cortical [3H] paroxetine binding to nerve terminal 5-HT transporters. MDMA-induced 5-HT loss was enhanced in animals following chronic fluoxetine administration. Elimination of fluoxetine and its metabolite norfluoxetine from the brain abolished this interaction between MDMA and fluoxetine treatment. Fluoxetine administration reduced both 5-HIAA and the 5-HIAA:5-HT metabolism ratio, which was attenuated in animals pre-treated with MDMA. Overall the results show that MDMA induces long-term 5-HT loss in the rodent brain and consequently diminishes behaviour and reductions in 5-HT metabolism induced by the antidepressant fluoxetine. These results have potential clinical relevance
Treatment of Chronic Enterovirus Encephalitis With Fluoxetine in a Patient With X-Linked Agammaglobulinemia.

PubMed

Gofshteyn, Jacqueline; Cárdenas, Ana María; Bearden, David

2016-11-01

Enterovirus may result in a devastating chronic encephalitis in immunocompromised patients, particularly in patients with X-linked agammaglobulinemia. Prognosis for patients with chronic enterovirus encephalitis is poor, almost invariably resulting in mortality without specific treatment. There are currently no approved antiviral agents for enterovirus, but the antidepressant drug fluoxetine has been identified through library-based compound screening as a potential anti-enteroviral agent in vitro. However, use of fluoxetine has not previously been studied in humans with enteroviral disease. A five year old boy with X-linked agammaglobulinemia presented with progressive neurological deterioration and was found to have chronic enterovirus encephalitis by brain biopsy. He failed to respond to standard treatment with high dose intravenous immunoglobulin, but showed stabilization and improvement following treatment with fluoxetine. This is the first report to describe the use of fluoxetine as a potential therapy for chronic enterovirus infection. Further investigation of fluoxetine as a treatment option for chronic enterovirus encephalitis is necessary. Copyright © 2016 Elsevier Inc. All rights reserved.
Treatment of depression in older adults beyond fluoxetine

PubMed Central

Wagner, Gabriela Arantes

2015-01-01

This review aimed to discuss the importance of the comprehensive treatment of depression among older adults in Brazil. The abuse of selective serotonin reuptake inhibitors, including fluoxetine hydrochloride, as antidepressants has been considered a serious public health problem, particularly among older adults. Despite the consensus on the need for a comprehensive treatment of depression in this population, Brazil is still unprepared. The interface between pharmacotherapy and psychotherapy is limited due to the lack of healthcare services, specialized professionals, and effective healthcare planning. Fluoxetine has been used among older adults as an all-purpose drug for the treatment of depressive disorders because of psychosocial adversities, lack of social support, and limited access to adequate healthcare services for the treatment of this disorder. Preparing health professionals is a sine qua non for the reversal of the age pyramid, but this is not happening yet. PMID:25830872
The relationship between symptom relief and functional improvement during acute fluoxetine treatment for patients with major depressive disorder.

PubMed

Lin, Ching-Hua; Chou, Li-Shiu; Chen, Ming-Chao; Chen, Cheng-Chung

2015-08-15

The purpose of this study was to compare the rate of symptom relief to functional improvement and examine the relationships between symptom relief and functional improvement during the acute phase of treatment. A total of 131 acutely ill inpatients with major depressive disorder were enrolled to receive 20mg of fluoxetine daily for 6 weeks. Symptom severity, using the 17-item Hamilton Depression Rating Scale (HAMD-17), and functioning, using the Modified Work and Social Adjustment Scale (MWSAS), were measured regularly. The outcome measures were the HAMD-17 score and MWSAS score at weeks 1, 2, 3, 4, and 6. We compared the effect size and the reduction rate of HAMD-17 to those of MWSAS at week 1, 2, 3, 4, and 6. Structural equation modeling was used to examine relationships among the study variables. Of the 131 participants, 126 had at least one post-baseline assessment at week 1 and were included in the analysis. The HAMD-17 had a larger effect size and reduction rate than the MWSAS at weeks 1, 2, 3, 4, and 6. Parsimonious model satisfied all indices of goodness-of-fit (Chi-Square/df=1.479, TLI=0.978, CFI=0.986, RMSEA=0.062) and had all paths with significant path coefficients. MWSAS at week 0 predicted HAMD-17 at week 1. This was an open-labeled study with small sample size. Depressive symptoms improved more quickly than functioning during the acute phase of treatment. Depressive symptoms and functional impairment are distinct domains, and should be assessed independently. Copyright © 2015 Elsevier B.V. All rights reserved.
Randomized, double-blind, placebo-controlled trial of fluoxetine treatment for elderly patients with dysthymic disorder.

PubMed

Devanand, D P; Nobler, Mitchell S; Cheng, Jocelyn; Turret, Nancy; Pelton, Gregory H; Roose, Steven P; Sackeim, Harold A

2005-01-01

The authors compared the efficacy and side effects of fluoxetine and placebo in elderly outpatients with dysthymic disorder. Patients were randomly assigned to fluoxetine (20 mg-60 mg/day) or placebo for 12 weeks in a double-blind trial. Of 90 randomized patients, 71 completed the trial. In the intent-to-treat sample, random regression analyses of the Hamilton Rating Scale for Depression (Ham-D; 24-item) and Cornell Dysthymia Rating Scale (CDRS) scores at each visit produced significant time x treatment group interactions favoring the fluoxetine group. Analysis of percentage change in Ham-D scores yielded no effect for treatment group, but a similar analysis of percentage change in CDRS scores yielded a main effect for treatment group, favoring fluoxetine over placebo. In the intent-to-treat sample, response rates were 27.3% for fluoxetine and 19.6% for placebo. In the completer sample, response rates were 37.5% for fluoxetine and 23.1% for placebo. Fluoxetine had limited efficacy in elderly dysthymic patients. The clinical features of elderly dysthymic patients are typically distinct from those of dysthymic disorder in young adults, and the findings suggest that treatments effective for young adult dysthymic patients may not be as useful in elderly dysthymic patients. Further research is needed to identify efficacious treatments for elderly patients with dysthymic disorder, and investigative tools such as electronic/computerized brain scans and neuropsychological testing may help identify the factors that moderate antidepressant treatment response and resistance.
Differential regulation of catecholamine synthesis and transport in rat adrenal medulla by fluoxetine treatment.

PubMed

Spasojevic, Natasa; Jovanovic, Predrag; Dronjak, Sladjana

2015-03-01

We have recently shown that chronic fluoxetine treatment acted significantly increasing plasma norepinephrine and epinephrine concentrations both in control and chronically stressed adult male rats. However, possible effects of fluoxetine on catecholamine synthesis and re-uptake in adrenal medulla have been largely unknown. In the present study the effects of chronic fluoxetine treatment on tyrosine hydroxylase, a rate-limiting enzyme in catecholamine synthesis, as well as a norepinephrine transporter and vesicular monoamine transporter 2 gene expressions in adrenal medulla of animals exposed to chronic unpredictable mild stress (CUMS) for 4 weeks, were investigated. Gene expression analyses were performed using a real-time quantitative reverse transcription-PCR. Chronically stressed animals had increased tyrosine hydroxylase mRNA levels and decreased expression of both transporters. Fluoxetine increased tyrosine hydroxylase and decreased norepinephrine transporter gene expression in both unstressed and CUMS rats. These findings suggest that chronic fluoxetine treatment increased plasma catecholamine levels by affecting opposing changes in catecholamine synthesis and uptake.

Temporal variability of glucocorticoid receptor activity is functionally important for the therapeutic action of fluoxetine in the hippocampus.

PubMed

Lee, M-S; Kim, Y-H; Park, W-S; Park, O-K; Kwon, S-H; Hong, K S; Rhim, H; Shim, I; Morita, K; Wong, D L; Patel, P D; Lyons, D M; Schatzberg, A F; Her, S

2016-02-01

Previous studies have shown inconsistent results regarding the actions of antidepressants on glucocorticoid receptor (GR) signalling. To resolve these inconsistencies, we used a lentiviral-based reporter system to directly monitor rat hippocampal GR activity during stress adaptation. Temporal GR activation was induced significantly by acute stress, as demonstrated by an increase in the intra-individual variability of the acute stress group compared with the variability of the non-stress group. However, the increased intra-individual variability was dampened by exposure to chronic stress, which was partly restored by fluoxetine treatment without affecting glucocorticoid secretion. Immobility in the forced-swim test was negatively correlated with the intra-individual variability, but was not correlated with the quantitative GR activity during fluoxetine therapy; this highlights the temporal variability in the neurobiological links between GR signalling and the therapeutic action of fluoxetine. Furthermore, we demonstrated sequential phosphorylation between GR (S224) and (S232) following fluoxetine treatment, showing a molecular basis for hormone-independent nuclear translocation and transcriptional enhancement. Collectively, these results suggest a neurobiological mechanism by which fluoxetine treatment confers resilience to the chronic stress-mediated attenuation of hypothalamic-pituitary-adrenal axis activity.
Fluoxetine. A pharmacoeconomic review of its use in depression.

PubMed

Wilde, M I; Benfield, P

1998-05-01

Depressive illness is a common, often unrecognised and untreated condition with substantial associated costs, particularly indirect costs (e.g. lost productivity and absenteeism). The improved tolerability profile of fluoxetine and associated lower discontinuation rates, the relative safety of the drug in overdosage and its similar efficacy compared with tricyclic antidepressants have provided the main rationale for using this agent in depressed patients. Pharmacoeconomic analyses of fluoxetine have mainly sought to determine whether its higher acquisition cost in comparison with tricyclic antidepressants can be offset by reductions in other costs and whether the use of this agent as first-line therapy can be justified. Studies have also attempted to determine whether the selective serotonin reuptake inhibitors (SSRIs) can be distinguished from one another on pharmacoeconomic grounds; overall efficacy and tolerability of these agents appear to be similar, although tolerability data are conflicting. Most analyses have been of a retrospective database or clinical decision analytic model design; two prospective trials (one conducted in a naturalistic setting) have been conducted. These studies have mainly considered direct treatment costs only from the perspective of the healthcare payer. Available evidence suggests that overall total direct healthcare costs for patients who start antidepressant therapy with fluoxetine are similar to, or lower than, those for patients who start therapy with tricyclic agents or other SSRIs. Offsetting of the higher acquisition cost of fluoxetine compared with that of tricyclic agents may be accounted for by lower in- and outpatient costs with fluoxetine, a possible lower risk of absenteeism from work and lower mean total medical costs associated with acute overdosage. Between-treatment differences in drug use patterns may also, in part, explain the observed differences in total healthcare costs between fluoxetine and other
An analysis of the effects of acute and chronic fluoxetine on extracellular norepinephrine in the rat hippocampus during stress.

PubMed

Page, M E; Abercrombie, E D

1997-06-01

The locus coeruleus (LC) noradrenergic system is activated by a range of arousing and stressful stimuli. The serotonergic inputs to this structure have been shown to attenuate LC activation under some conditions. The present study examined the effect of fluoxetine, a selective serotonin reuptake inhibitor (SSRI) known to be a clinically effective antidepressant, on basal and stress-induced norepinephrine (NE) release. Basal and stress-induced NE efflux in the rat hippocampus were assessed using in vivo microdialysis techniques. The effect of a 30 minute tailpinch stressor on extracellular concentration of NE was compared in rats treated with fluoxetine either once prior to tailpinch or twice daily for 14 days and, respectively, in unhandled controls and vehicle-treated control animals. A single fluoxetine injection prior to tailpinch did not significantly alter the tailpinch-induced increase of extracellular NE as compared to naive controls. However, there was an enhanced NE response to tailpinch in chronic fluoxetine versus chronic vehicle-treated control rats. Thus, acute blockade of 5-HT uptake by fluoxetine does not affect NE release in response to tailpinch stress. Chronic fluoxetine administration, however, results in a potentiated evoked response of the LC-NE system. One action of chronic fluoxetine, which may relate to therapeutic efficacy, is an increase in responsivity of LC neurons.
Amelioration of ongoing experimental autoimmune encephalomyelitis with fluoxetine.

PubMed

Bhat, Roopa; Mahapatra, Sidharth; Axtell, Robert C; Steinman, Lawrence

2017-12-15

In patients with multiple sclerosis, the selective serotonin reuptake inhibitor, fluoxetine, resulted in less acute disease activity. We tested the immune modulating effects of fluoxetine in a mouse model of multiple sclerosis, i.e. experimental autoimmune encephalomyelitis (EAE). We show that fluoxetine delayed the onset of disease and reduced clinical paralysis in mice with established disease. Fluoxetine had abrogating effects on proliferation of immune cells and inflammatory cytokine production by both antigen-presenting cells and T cells. Specifically, in CD 4 T cells, fluoxetine increased Fas-induced apoptosis. We conclude that fluoxetine possesses immune-modulating effects resulting in the amelioration of symptoms in EAE. Copyright © 2017 Elsevier B.V. All rights reserved.
Fluoxetine regulates mTOR signalling in a region-dependent manner in depression-like mice

PubMed Central

Liu, Xiao-Long; Luo, Liu; Mu, Rong-Hao; Liu, Bin-Bin; Geng, Di; Liu, Qing; Yi, Li-Tao

2015-01-01

Previous studies have demonstrated that the mammalian target of rapamycin (mTOR) signaling pathway has an important role in ketamine-induced, rapid antidepressant effects despite the acute administration of fluoxetine not affecting mTOR phosphorylation in the brain. However, the effects of long-term fluoxetine treatment on mTOR modulation have not been assessed to date. In the present study, we examined whether fluoxetine, a type of commonly used antidepressant agent, alters mTOR signaling following chronic administration in different brain regions, including the frontal cortex, hippocampus, amygdala and hypothalamus. We also investigated whether fluoxetine enhanced synaptic protein levels in these regions via the activation of the mTOR signaling pathway and its downstream regulators, p70S6K and 4E-BP-1. The results indicated that chronic fluoxetine treatment attenuated the chronic, unpredictable, mild stress (CUMS)-induced mTOR phosphorylation reduction in the hippocampus and amygdala of mice but not in the frontal cortex or the hypothalamus. Moreover, the CUMS-decreased PSD-95 and synapsin I levels were reversed by fluoxetine, and these effects were blocked by rapamycin only in the hippocampus. In conclusion, our findings suggest that chronic treatment with fluoxetine can induce synaptic protein expression by activating the mTOR signaling pathway in a region-dependent manner and mainly in the hippocampus. PMID:26522512
Fluoxetine regulates mTOR signalling in a region-dependent manner in depression-like mice.

PubMed

Liu, Xiao-Long; Luo, Liu; Mu, Rong-Hao; Liu, Bin-Bin; Geng, Di; Liu, Qing; Yi, Li-Tao

2015-11-02

Previous studies have demonstrated that the mammalian target of rapamycin (mTOR) signaling pathway has an important role in ketamine-induced, rapid antidepressant effects despite the acute administration of fluoxetine not affecting mTOR phosphorylation in the brain. However, the effects of long-term fluoxetine treatment on mTOR modulation have not been assessed to date. In the present study, we examined whether fluoxetine, a type of commonly used antidepressant agent, alters mTOR signaling following chronic administration in different brain regions, including the frontal cortex, hippocampus, amygdala and hypothalamus. We also investigated whether fluoxetine enhanced synaptic protein levels in these regions via the activation of the mTOR signaling pathway and its downstream regulators, p70S6K and 4E-BP-1. The results indicated that chronic fluoxetine treatment attenuated the chronic, unpredictable, mild stress (CUMS)-induced mTOR phosphorylation reduction in the hippocampus and amygdala of mice but not in the frontal cortex or the hypothalamus. Moreover, the CUMS-decreased PSD-95 and synapsin I levels were reversed by fluoxetine, and these effects were blocked by rapamycin only in the hippocampus. In conclusion, our findings suggest that chronic treatment with fluoxetine can induce synaptic protein expression by activating the mTOR signaling pathway in a region-dependent manner and mainly in the hippocampus.
Fluoxetine treatment reverses the intergenerational impact of maternal separation on fear and anxiety behaviors.

PubMed

Xiong, Gui-Jing; Yang, Yuan; Cao, Jun; Mao, Rong-Rong; Xu, Lin

2015-05-01

Early life stress increases risks of fear and anxiety related disorders in adulthood, which may be alleviated by fluoxetine treatment. However, the intergenerational impacts of maternal separation (MS) on fear and anxiety behaviors from father to their offspring are little known. And the potential effects of fluoxetine treatment on the intergenerational transmission have not been well tested. Here, we investigated whether fluoxetine can reverse the intergenerational effects of MS on fear and anxiety behaviors. The first generation (F1) male rats were exposed to MS 3 h daily from postnatal day 2-14 and then treated with fluoxetine for four weeks during adulthood before fear conditioning. We found that maternal separation significantly impaired contextual fear extinction in F1 adult male rats but not in their second generation (F2). Although no obvious effects of MS on anxiety were observed in F1 male rats, the F2 offspring displayed a phenotype of low anxiety-like behaviors despite they were reared in normal condition. Fluoxetine treatment in F1 males not only reversed the impairment of fear extinction in F1 males but also the low anxiety-like behaviors in their F2 offspring. These findings highlight the intergenerational impacts of early life stress on fear and anxiety behaviors, and provide a new sight of the intergenerational effect of fluoxetine therapy for early life stress related mental problems. Copyright © 2015 Elsevier Ltd. All rights reserved.
Leptin receptor deficiency confers resistance to behavioral effects of fluoxetine and desipramine via separable substrates.

PubMed

Guo, M; Lu, X-Y

2014-12-02

Depression is a complex, heterogeneous mental disorder. Currently available antidepressants are only effective in about one-third to one-half of all patients. The mechanisms underlying antidepressant response and treatment resistance are poorly understood. Recent clinical evidence implicates the involvement of leptin in treatment response to antidepressants. In this study, we determined the functional role of the leptin receptor (LepRb) in behavioral responses to the selective serotonergic antidepressant fluoxetine and the noradrenergic antidepressant desipramine. While acute and chronic treatment with fluoxetine or desipramine in wild-type mice elicited antidepressant-like effects in the forced swim test, mice null for LepRb (db/db) displayed resistance to treatment with either fluoxetine or desipramine. Fluoxetine stimulated phosphorylation of Akt(Thr308) and GSK-3β(Ser9) in the hippocampus and prefrontal cortex (PFC) of wild-type mice but not in db/db mice. Desipramine failed to induce measurable changes in Akt, GSK-3β or ERK1/2 phosphorylation in the hippocampus and PFC, as well as hypothalamus of either genotype of mice. Deletion of LepRb specifically from hippocampal and cortical neurons resulted in fluoxetine insensitivity in the forced swim test and tail suspension test while leaving the response to desipramine intact. These results suggest that functional LepRb is critically involved in regulating the antidepressant-like behavioral effects of both fluoxetine and desipramine. The antidepressant effects of fluoxetine but not desipramine are dependent on the presence of functional LepRb in the hippocampus and cortex.
Diagnosis and Fluoxetine Treatment of Compulsive Behavior Disorder of Adults with Mental Retardation.

ERIC Educational Resources Information Center

Bodfish, James W.; Madison, James T.

1993-01-01

Ten adults with compulsive behavior disorder and six comparison subjects, all with mental retardation, were treated using the medication fluoxetine. Seven of the 10 experimental subjects responded favorably to fluoxetine treatment; none of the comparison subjects responded favorably to the medication. There appeared to be a relation between…
Fluoxetine Alleviates Behavioral Depression while Decreasing Acetylcholine Release in the Nucleus Accumbens Shell

PubMed Central

Chau, David T; Rada, Pedro V; Kim, Kay; Kosloff, Rebecca A; Hoebel, Bartley G

2011-01-01

Selective serotonin reuptake inhibitors, such as fluoxetine, have demonstrated the ability to alleviate behavioral depression in the forced swim test; however, the sites and mechanisms of their actions remain to be further elucidated. Previous studies have suggested that behavioral depression in the swim test is mediated in part by acetylcholine (ACh) stimulating the cholinergic M1 receptors in the nucleus accumbens (NAc) shell. The current study tested whether acute, local, and chronic, subcutaneous fluoxetine treatments increase escape motivation during the swim test while simultaneously lowering extracellular ACh in the NAc shell. Experiment 1: Fluoxetine (1.0 mM) infused unilaterally in the NAc shell for 40 min reduced extracellular ACh while simultaneously increasing swimming time. Experiment 2: Fluoxetine (0.2, 0.5, and 0.75 mM) infused bilaterally in the NAc shell on day 3 dose-dependently decreased immobility and increased the total escape attempts (swimming and climbing) compared with Ringer given on day 2. Experiment 3: Fluoxetine (0.5 mM) infused bilaterally in the NAc for 40 min did not affect activities in an open field. Experiment 4: Chronic systemic fluoxetine treatment decreased immobility scores and increased total escape attempt scores compared with control saline treatment. In all, 14 days after the initial swim test, basal extracellular ACh in the shell was still elevated in the saline-treated group, but not in the fluoxetine-treated group. In summary, these data suggest that one of the potential mechanisms by which fluoxetine alleviates behavioral depression in the forced swim test may be to suppress cholinergic activities in the NAc shell. PMID:21525864
Fluoxetine versus Vitex agnus castus extract in the treatment of premenstrual dysphoric disorder.

PubMed

Atmaca, Murad; Kumru, Selahattin; Tezcan, Ertan

2003-04-01

Clinical trials have demonstrated that serotonin reuptake inhibitors (SRIs) and the extract of Vitex agnus castus are effective for the treatment of premenstrual dysphoric disorder (PMDD). However, to the best of our knowledge, there has been no study comparing the efficacy of the SRIs with Vitex agnus castus (AC) extract. Therefore, the aim of the present study was to compare the efficacy of fluoxetine, a selective serotonin reuptake inhibitor (SSRI), with that of the AC extract, a natural choice. After a period of 2 screening months to screen the patients for suitability, 41 patients with PMDD according to DSM-IV were recruited into the study. The patients were randomized to fluoxetine or AC for 2 months of single-blind, rater- blinded and prospective treatment period. The outcome measures included the Penn daily symptom report (DSR), the Hamilton depression rating scale (HAM-D), and the clinical global impression-severity of illness (CGI-SI) and -improvement (CGI-I) scales. At endpoint, using the clinical criterion for improvement, a similar percentage of patients responded to fluoxetine (68.4%, n = 13) and AC (57.9%, n = 11). There was no statistically significant difference between the groups with respect to the rate of responders. This preliminary study suggests that patients with PMDD respond well to treatment with both fluoxetine and AC. However, fluoxetine was more effective for psychological symptoms while the extract diminished the physical symptoms. Copyright 2002 John Wiley & Sons, Ltd.
Chronic fluoxetine treatment accelerates kindling epileptogenesis in mice independently of 5-HT2A receptors.

PubMed

Li, Crystal; Silva, Juliana; Ozturk, Ezgi; Dezsi, Gabriella; O'Brien, Terence J; Renoir, Thibault; Jones, Nigel C

2018-06-01

Patients with epilepsy often have mood disorders, and these are commonly treated with antidepressant drugs. Although these drugs are often successful in mitigating depressive symptoms, how they affect the epileptogenic processes has been little studied. Recent evidence has demonstrated that treatment with selective serotonin reuptake inhibitor (SSRI) antidepressant drugs adversely promotes epileptogenesis, which may be of great concern considering the number of patients exposed to these drugs. This study investigated 5-HT 2A receptor signaling as a potential mechanism driving the pro-epileptogenic effects of the prototypical SSRI fluoxetine. Male homozygous 5-HT 2A receptor knockout mice or wild-type littermates (n = 9-14/group) were treated with continuous fluoxetine (10 mg kg -1 d -1 , sc) or vehicle and subjected to electrical kindling of the amygdala. Compared to vehicle, fluoxetine treatment accelerated kindling epileptogenesis (P < .001), but there was no effect of genotype (P = .75), or any treatment x genotype interaction observed (P = .90). Of interest, fluoxetine treatment increased afterdischarge thresholds in both genotypes (P = .007). We conclude that treatment with fluoxetine promotes epileptogenesis in mice, but this effect is not mediated by 5-HT 2A receptors. This suggests that antidepressants may accelerate the onset of acquired epilepsy in patients who have experienced epileptogenic cerebral insults. Wiley Periodicals, Inc. © 2018 International League Against Epilepsy.
Effects of combined nicotine and fluoxetine treatment on adult hippocampal neurogenesis and conditioned place preference.

PubMed

Faillace, M P; Zwiller, J; Bernabeu, R O

2015-08-06

Adult neurogenesis occurs in mammals within the dentate gyrus, a hippocampal subarea. It is known to be induced by antidepressant treatment and reduced in response to nicotine administration. We checked here whether the antidepressant fluoxetine would inverse the decrease in hippocampal neurogenesis caused by nicotine. It is shown that repeated, but not a single injection of rats with fluoxetine was able to abolish the decrease in adult dentate cell proliferation produced by nicotine treatment. We measured the expression of several biochemical parameters known to be associated with neurogenesis in the dentate gyrus. Both drugs increased the expression of p75 neurotrophin receptor, which promotes proliferation and early maturation of dentate gyrus cells. Using the conditioned place preference (CPP) paradigm, we also gave both drugs in a context in which their rewarding properties could be measured. Fluoxetine produced a significant but less robust CPP than nicotine. A single injection of fluoxetine was found to reduce nicotine-induced CPP. Moreover, the rewarding properties of nicotine were completely abolished in response to repeated fluoxetine injections. Expression of nicotine-induced CPP was accompanied by an increase of phospho-CREB (cyclic AMP-responsive element-binding protein) and HDAC2 (histone deacetylase 2) expression in the nucleus accumbens. The data suggest that fluoxetine reward, as opposed to nicotine reward, depends on dentate gyrus neurogenesis. Since fluoxetine was able to disrupt the association between nicotine and the environment, this antidepressant may be tested as a treatment for nicotine addiction using cue exposure therapy. Copyright © 2015 IBRO. Published by Elsevier Ltd. All rights reserved.
Evaluation of antidepressant like activity of curcumin and its combination with fluoxetine and imipramine: an acute and chronic study.

PubMed

Sanmukhani, Jayesh; Anovadiya, Ashish; Tripathi, Chandrabhanu B

2011-01-01

Curcumin is the active ingredient of commonly used spice Curuma longa Linn. In the present study, the antidepressant like activity of curcumin and its combination with fluoxetine and imipramine was studied in acute model (three doses 24, 5 and 1 h before test) of forced swimming test (FST) in glass jar and tail suspension test (TST) in mice and in chronic model (14 day study) of FST with water wheel in rats. All the tests were carried out in the following seven groups (n = 6 in each group), drugs being given orally (doses for mice): Group 1 (vehicle), group 2 (curcumin 50 mg/kg), group 3 (curcumin 100 mg/kg), group 4 (fluoxetine 20 mg/kg), group 5 (imipramine 15 mg/kg), group 6 (curcumin 100 mg/kg plus fluoxetine 20 mg/kg) and group 7 (curcumin 100 mg/kg plus imipramine 15 mg/kg). Equivalent doses for rats were used. Both the acute model of FST and TST, and the chronic model of FST with water wheel showed significant antidepressant like activity of curcumin in 100 mg/kg dose as compared to vehicle control (p < 0.05). The effect of curcumin (100 mg/kg) was similar to that of fluoxetine and imipramine (p > 0.05) but its addition to fluoxetine and imipramine did not improve their antidepressant activity (p > 0.05). Curcumin increased both the swimming and climbing behavior in FST, thus its antidepressant like activity could be due to an increase in serotonin, norepinephrine and dopamine levels in the brain. Curcumin can be a useful antidepressant especially in cases which respond to drugs having mixed effects on serotonin and catecholamines levels in the brain.
Augmenting Cognitive Behavior Therapy for School Refusal with Fluoxetine: A Randomized Controlled Trial.

PubMed

Melvin, Glenn A; Dudley, Amanda L; Gordon, Michael S; Klimkeit, Ester; Gullone, Eleonora; Taffe, John; Tonge, Bruce J

2017-06-01

This study investigates whether the augmentation of cognitive behavior therapy (CBT) with fluoxetine improves outcomes in anxious school refusing adolescents (11-16.5 years). Sixty-two participants were randomly allocated to CBT alone, CBT + fluoxetine or CBT + placebo. All treatments were well tolerated; with one suicide-attempt in the CBT + placebo group. All groups improved significantly on primary (school attendance) and secondary outcome measures (anxiety, depression, self-efficacy and clinician-rated global functioning); with gains largely maintained at 6-months and 1-year. Few participants were anxiety disorder free after acute treatment. During the follow-up period anxiety and depressive disorders continued to decline whilst school attendance remained stable, at around 54 %. The only significant between-group difference was greater adolescent-reported treatment satisfaction in the CBT + fluoxetine group than the CBT alone group. These results indicate the chronicity of school refusal, and the need for future research into how to best improve school attendance rates.
Fluoxetine treatment is effective in a rat model of childhood-induced post-traumatic stress disorder.

PubMed

Ariel, Lior; Inbar, Sapir; Edut, Schachaf; Richter-Levin, Gal

2017-11-30

Although selective serotonin reuptake inhibitors (SSRIs) are first-line treatment for post-traumatic stress disorder (PTSD) patients, their therapeutic efficacy is limited. Childhood adversities are considered a risk factor for developing PTSD in adulthood but may trigger PTSD without additional trauma in some individuals. Nevertheless, just as childhood is considered a vulnerable period it may also be an effective period for preventive treatment. Using a rat model of childhood-induced PTSD, pre-pubertal stress (juvenile stress, JVS), we compared the therapeutic effects of fluoxetine and examined the effectiveness of 1 month of fluoxetine treatment following JVS and into adulthood compared to treatment in adulthood. Since not all individuals develop PTSD following a trauma, comparing only group means is not the adequate type of analysis. We employed a behavioral profiling approach, which analyzes individual differences compared to the normal behavior of a control group. Animals exposed to JVS exhibited a higher proportion of affected animals as measured using the elevated plus maze 8 weeks after JVS. Fluoxetine treatment following the JVS significantly decreased the proportion of affected animals as measured in adulthood. Fluoxetine treatment in adulthood was not effective. The results support the notion that childhood is not only a vulnerable period but also an effective period for preventive treatment.
Fluoxetine Inhibits Natural Decay of Long-Term Memory via Akt/GSK-3β Signaling.

PubMed

Yi, Jee Hyun; Zhang, JiaBao; Ko, Sang Yoon; Kwon, Huiyoung; Jeon, Se Jin; Park, Se Jin; Jung, Jiwook; Kim, Byung C; Lee, Young Choon; Kim, Dong Hyun; Ryu, Jong Hoon

2018-02-09

Understanding the mechanisms underlying the natural decay of long-term memory can help us find means of extending the duration of long-term memory. However, the neurobiological processes involved in the decay of long-term memory are poorly understood. In the present study, we examined the effect of acute and chronic treatment of fluoxetine on natural decay of long-term memory and the possible mechanism. Late administration of fluoxetine prolonged the persistence of long-term memory in mice, as demonstrated by object location recognition and Barnes maze tests. Fluoxetine altered Akt/glycogen synthase kinase-3β (GSK-3β)/β-catenin signaling in the hippocampus. Late short- and long-term pharmacological inhibition of GSK-3β mimicked the effect of fluoxetine on memory persistence. Pharmacological inhibition of Akt blocked the effect of fluoxetine on memory persistence. Finally, late infusion of fluoxetine increased hippocampal long-term potentiation (LTP) and pharmacological inhibition of GSK-3β blocked the natural decline in LTP. These results demonstrate that GSK-3β might be a key molecule in memory decay process, and fluoxetine extends the period of long-term memory maintenance via Akt/GSK-3β signaling.
Chronic fluoxetine treatment partly attenuates the long-term anxiety and depressive symptoms induced by MDMA ('Ecstasy') in rats.

PubMed

Thompson, Murray R; Li, Kong M; Clemens, Kelly J; Gurtman, Clint G; Hunt, Glenn E; Cornish, Jennifer L; McGregor, Iain S

2004-04-01

Use of the drug 3,4-methylenedioxymethamphetamine (MDMA, 'Ecstasy') can have long-term adverse effects on emotion in both humans and laboratory animals. The present study examined whether chronic treatment with the antidepressant drug fluoxetine could reverse such effects. Male Wistar rats were briefly exposed to MDMA (4 x 5 mg/kg over 4 h) or vehicle on 2 consecutive days. Approximately 9-12 weeks later, half of the rats received a dose of approximately 6 mg/kg/day fluoxetine in their drinking water for a 5-week period. Fluoxetine administration reduced fluid intake and body weight in MDMA and vehicle pretreated rats. After several weeks of fluoxetine treatment, rats were assessed on the social interaction test, the emergence test of anxiety and the forced swim model of depression. MDMA pretreated rats showed reduced social interaction, increased anxiety on the emergence test, and increased immobility and decreased active responses in the forced swim test. Fluoxetine treatment reversed MDMA-induced anxiety in the emergence test and depressive-like effects in the forced swim test, yet exhibited no effects on the social interaction test. MDMA pretreated rats had decreased 5-HT and 5-HIAA levels in limbic and cortical regions, and decreased density of serotonin transporter sites in the cortex. Fluoxetine treatment did not greatly affect 5-HT levels in MDMA pretreated rats, but significantly decreased 5-HIAA levels in all brain sites examined. Postmortem blood serum levels of fluoxetine and norfluoxetine did not differ in MDMA and vehicle pretreated rats. These results indicate that fluoxetine may provide a treatment option for some of the deleterious long-term effects resulting from MDMA exposure.
Atorvastatin and Fluoxetine Prevent Oxidative Stress and Mitochondrial Dysfunction Evoked by Glutamate Toxicity in Hippocampal Slices.

PubMed

Ludka, Fabiana K; Dal-Cim, Tharine; Binder, Luisa Bandeira; Constantino, Leandra Celso; Massari, Caio; Tasca, Carla I

2017-07-01

Atorvastatin has been shown to exert a neuroprotective action by counteracting glutamatergic toxicity. Recently, we have shown atorvastatin also exerts an antidepressant-like effect that depends on both glutamatergic and serotonergic systems modulation. Excitotoxicity is involved in several brain disorders including depression; thus, it is suggested that antidepressants may target glutamatergic system as a final common pathway. In this study, a comparison of the mechanisms involved in the putative neuroprotective effect of a repetitive atorvastatin or fluoxetine treatment against glutamate toxicity in hippocampal slices was performed. Adult Swiss mice were treated with atorvastatin (10 mg/kg, p.o.) or fluoxetine (10 mg/kg, p.o.), once a day during seven consecutive days. On the eighth day, animals were killed and hippocampal slices were obtained and subjected to an in vitro protocol of glutamate toxicity. An acute treatment of atorvastatin or fluoxetine was not neuroprotective; however, the repeated atorvastatin or fluoxetine treatment prevented the decrease in cellular viability induced by glutamate in hippocampal slices. The loss of cellular viability induced by glutamate was accompanied by increased D-aspartate release, increased reactive oxygen species (ROS) and nitric oxide (NO) production, and impaired mitochondrial membrane potential. Atorvastatin or fluoxetine repeated treatment also presented an antidepressant-like effect in the tail suspension test. Atorvastatin or fluoxetine treatment was effective in protecting mice hippocampal slices from glutamate toxicity by preventing the oxidative stress and mitochondrial dysfunction.
Chronic fluoxetine dissociates contextual from auditory fear memory.

PubMed

Sanders, Jeff; Mayford, Mark

2016-10-06

Fluoxetine is a medication used to treat Major Depressive Disorder and other psychiatric conditions. These experiments studied the effects of chronic fluoxetine treatment on the contextual versus auditory fear memory of mice. We found that chronic fluoxetine treatment of adult mice impaired their contextual fear memory, but spared auditory fear memory. Hippocampal perineuronal nets, which are involved in contextual fear memory plasticity, were unaltered by fluoxetine treatment. These data point to a selective inability to form contextual fear memory as a result of fluoxetine treatment, and they suggest that a blunting of hippocampal-mediated aversive memory may be a therapeutic action for this medication. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Effects of Chronic Fluoxetine Treatment on Neurogenesis and Tryptophan Hydroxylase Expression in Adolescent and Adult Rats

PubMed Central

Meerhoff, Gideon F.

2014-01-01

The antidepressant drug fluoxetine (Prozac) has been increasingly prescribed to children and adolescents with depressive disorders despite a lack of thorough understanding of its therapeutic effects in the paediatric population and of its putative neurodevelopmental effects. Within the framework of PRIOMEDCHILD ERA-NET, we investigated; a) effects of chronic fluoxetine treatment on adult hippocampal neurogenesis, a structural readout relevant for antidepressant action and hippocampal development; b) effects on tryptophan hydroxylase (TPH) expression, a measure of serotonin synthesis; c) whether treatment effects during adolescence differed from treatment at an adult age, and d) whether they were subregion-specific. Stereological quantification of the number of proliferating (Ki-67+) cells and of the number of young migratory neurons (doublecortin+), revealed a significant age-by-treatment interaction effect, indicating that fluoxetine affects both proliferation and neurogenesis in adolescent-treated rats differently than it does in adult-treated rats. In terms of subregional differences, fluoxetine enhanced proliferation mainly in the dorsal parts of the hippocampus, and neurogenesis in both the suprapyramidal and infrapyramidal blades of the dentate gyrus in adolescent-treated rats, while no such differences were seen in adult-treated rats. Fluoxetine exerted similar age-by-treatment interaction effects on TPH cells mainly in the ventral portion of the dorsal raphe nucleus. We conclude that fluoxetine exerts divergent effects on structural plasticity and serotonin synthesis in adolescent versus adult-treated rats. These preliminary data indicate a differential sensitivity of the adolescent brain to this drug and thus warrant further research into their behavioural and translational aspects. Together with recent related findings, they further call for caution in prescribing these drugs to the adolescent population. PMID:24827731
Effects of chronic fluoxetine treatment on neurogenesis and tryptophan hydroxylase expression in adolescent and adult rats.

PubMed

Klomp, Anne; Václavů, Lena; Meerhoff, Gideon F; Reneman, Liesbeth; Lucassen, Paul J

2014-01-01

The antidepressant drug fluoxetine (Prozac) has been increasingly prescribed to children and adolescents with depressive disorders despite a lack of thorough understanding of its therapeutic effects in the paediatric population and of its putative neurodevelopmental effects. Within the framework of PRIOMEDCHILD ERA-NET, we investigated; a) effects of chronic fluoxetine treatment on adult hippocampal neurogenesis, a structural readout relevant for antidepressant action and hippocampal development; b) effects on tryptophan hydroxylase (TPH) expression, a measure of serotonin synthesis; c) whether treatment effects during adolescence differed from treatment at an adult age, and d) whether they were subregion-specific. Stereological quantification of the number of proliferating (Ki-67+) cells and of the number of young migratory neurons (doublecortin+), revealed a significant age-by-treatment interaction effect, indicating that fluoxetine affects both proliferation and neurogenesis in adolescent-treated rats differently than it does in adult-treated rats. In terms of subregional differences, fluoxetine enhanced proliferation mainly in the dorsal parts of the hippocampus, and neurogenesis in both the suprapyramidal and infrapyramidal blades of the dentate gyrus in adolescent-treated rats, while no such differences were seen in adult-treated rats. Fluoxetine exerted similar age-by-treatment interaction effects on TPH cells mainly in the ventral portion of the dorsal raphe nucleus. We conclude that fluoxetine exerts divergent effects on structural plasticity and serotonin synthesis in adolescent versus adult-treated rats. These preliminary data indicate a differential sensitivity of the adolescent brain to this drug and thus warrant further research into their behavioural and translational aspects. Together with recent related findings, they further call for caution in prescribing these drugs to the adolescent population.
Moderators of fluoxetine treatment response for children and adolescents with comorbid depression and substance use disorders.

PubMed

Hirschtritt, Matthew E; Pagano, Maria E; Christian, Kelly M; McNamara, Nora K; Stansbrey, Robert J; Lingler, Jacqui; Faber, Jon E; Demeter, Christine A; Bedoya, Denise; Findling, Robert L

2012-06-01

Our recent 8-week, randomized, placebo-controlled trial of fluoxetine in adolescents (ages 12-17 years) with comorbid depression and substance use disorder (SUD) did not detect a significant antidepressant treatment effect. The purpose of this secondary analysis was to explore moderators of the effect of fluoxetine in this sample. Static moderators measured at baseline were depression chronicity and hopelessness severity; time-varying moderators measured at baseline and weekly during the 8-week trial period were alcohol and marijuana use severity. Treatment effects on depression outcomes were examined among moderating subgroups in random effects regression models. Subjects assigned to fluoxetine treatment with chronic depression at baseline (p = .04) or no more than moderate alcohol use during the trial (p = .04) showed significantly greater decline in depression symptoms in comparison to placebo-assigned subgroups. The current analysis suggests that youth with chronic depression and no more than moderate alcohol consumption are likely to respond better to treatment with fluoxetine compared with placebo than youth with transient depression and heavy alcohol use. Copyright © 2012 Elsevier Inc. All rights reserved.
Moderators of fluoxetine treatment response for children and adolescents with comorbid depression and substance use disorders

PubMed Central

Hirschtritt, Matthew E.; Pagano, Maria E.; Christian, Kelly M.; McNamara, Nora K.; Stansbrey, Robert J.; Lingler, Jacqui; Faber, Jon E.; Demeter, Christine A.; Bedoya, Denise; Findling, Robert L.

2012-01-01

Our recent 8-week, randomized, placebo-controlled trial of fluoxetine in adolescents (ages 12–17 years) with comorbid depression and substance use disorder (SUD) did not detect a significant antidepressant treatment effect. The purpose of this secondary analysis was to explore moderators of the effect of fluoxetine in this sample. Static moderators measured at baseline were depression chronicity and hopelessness severity; time-varying moderators measured at baseline and weekly during the 8-week trial period were alcohol and marijuana use severity. Treatment effects on depression outcomes were examined among moderating subgroups in random effects regression models. Subjects assigned to fluoxetine treatment with chronic depression at baseline (p = .04) or no more than moderate alcohol use during the trial (p = .04) showed significantly greater decline in depression symptoms in comparison to placebo-assigned subgroups. The current analysis suggests that youth with chronic depression and no more than moderate alcohol consumption are likely to respond better to treatment with fluoxetine compared with placebo than youth with transient depression and heavy alcohol use. PMID:22116008
Effects of acute and chronic exposures of fluoxetine on the Chinese fish, topmouth gudgeon Pseudorasbora parva.

PubMed

Chen, Hongxing; Zeng, Xiangfeng; Mu, Lei; Hou, Liping; Yang, Bin; Zhao, Jianliang; Schlenk, Daniel; Dong, Wu; Xie, Lingtian; Zhang, Qianru

2018-09-30

Fluoxetine is a selective serotonin reuptake inhibitor used as an antidepressant and has been frequently detected in aquatic environments. However, its effects in fish from Asia remain relatively less studied. In this study, the topmouth gudgeon Pseudorasbora parva was exposed to 0, 50, and 200 µg/L of fluoxetine for 4 h and 42 d. The effects of fluoxetine on biometrics were compared to biochemical endpoints indicative of stress in different fish tissues (brain, liver, gills and intestine) following exposures. In fish exposed for 42 d, lipid peroxidation endpoints were enhanced 80% in the liver and gills. Acetylcholinesterase (AChE) activity was increased 40% after exposure to 50 µg/L and 55% at 200 µg/L following 4 h exposure. In contrast AChE was increased 26% (at 50 µg/L) after 42 d of exposures. Enhanced ethoxyresorufin-O-deethylase activity (EROD) was detected only in fish exposed to 50 µg/L of fluoxetine for 4 h. The activity of α-glucosidase (α-Glu) was also induced (at 200 µg/L) after 4 h of exposure. After 4 h of exposure, the activities of proteases in the intestine were generally inhibited at 200 µg/L. Both 4 h and 42 d exposures resulted in an increased hepatosomatic index (HSI) but did not affect the condition factor (CF). Our results demonstrate that fluoxetine significantly altered biochemical endpoints in P. parva after acute exposure and the morphological changes in liver size were not observed until 42 d of exposure. Copyright © 2018. Published by Elsevier Inc.
Hypoglycemia associated with fluoxetine treatment in a patient with type 1 diabetes

PubMed Central

Biagetti, Betina; Corcoy, Rosa

2013-01-01

We report on a patient with type 1 diabetes mellitus who presented with recurrent episodes of hypoglycemia and a marked reduction in her daily insulin requirements after introduction of fluoxetine. This 25-year-old Caucasian woman had been followed up at the outpatient clinic for type 1 diabetes mellitus and pre-pregnancy care. She used a continuous subcutaneous insulin infusion with lispro and her daily insulin dose was 0.5 IU/kg per day. She had no chronic diabetic complications or hypoglycemia unawareness. Fluoxetine at a daily dose of 20 mg had been started because of depressive symptoms and within one week, she presented recurrent hypoglycemic episodes that prompted a progressive reduction in the insulin dose down to 0.3 IU/kg per day. The reduced insulin requirements continued during the period of fluoxetine treatment while glycated hemoglobin remained stable. She had no concurrent additional cause to explain the reduced insulin requirements. After fluoxetine was stopped, insulin requirements progressively increased and returned to the patient´s usual dose. PMID:24303494
Predictors of Treatment Response to Fluoxetine in PTSD Following a Recent History of War Zone Stress Exposure

DTIC Science & Technology

2012-07-01

Fluoxetine in PTSD Following a Recent History of War Zone Stress Exposure PRINCIPAL INVESTIGATOR: Paul B. Hicks, M.D., Ph.D...July 2011 – 30 June 2012 4. TITLE AND SUBTITLE 5a. CONTRACT NUMBER Predictors of Treatment Response to Fluoxetine in PTSD Following a Recent...war-zone duty has still not been determined. Consequently, this study was designed to conduct a controlled trial of fluoxetine as an early
Both chronic treatments by epothilone D and fluoxetine increase the short-term memory and differentially alter the mood status of STOP/MAP6 KO mice.

PubMed

Fournet, Vincent; de Lavilléon, Gaetan; Schweitzer, Annie; Giros, Bruno; Andrieux, Annie; Martres, Marie-Pascale

2012-12-01

Recent evidence underlines the crucial role of neuronal cytoskeleton in the pathophysiology of psychiatric diseases. In this line, the deletion of STOP/MAP6 (Stable Tubule Only Polypeptide), a microtubule-stabilizing protein, triggers various neurotransmission and behavioral defects, suggesting that STOP knockout (KO) mice could be a relevant experimental model for schizoaffective symptoms. To establish the predictive validity of such a mouse line, in which the brain serotonergic tone is dramatically imbalanced, the effects of a chronic fluoxetine treatment on the mood status of STOP KO mice were characterized. Moreover, we determined the impact, on mood, of a chronic treatment by epothilone D, a taxol-like microtubule-stabilizing compound that has previously been shown to improve the synaptic plasticity deficits of STOP KO mice. We demonstrated that chronic fluoxetine was either antidepressive and anxiolytic, or pro-depressive and anxiogenic, depending on the paradigm used to test treated mutant mice. Furthermore, control-treated STOP KO mice exhibited paradoxical behaviors, compared with their clear-cut basal mood status. Paradoxical fluoxetine effects and control-treated STOP KO behaviors could be because of their hyper-reactivity to acute and chronic stress. Interestingly, both epothilone D and fluoxetine chronic treatments improved the short-term memory of STOP KO mice. Such treatments did not affect the serotonin and norepinephrine transporter densities in cerebral areas of mice. Altogether, these data demonstrated that STOP KO mice could represent a useful model to study the relationship between cytoskeleton, mood, and stress, and to test innovative mood treatments, such as microtubule-stabilizing compounds. © 2012 The Authors Journal of Neurochemistry © 2012 International Society for Neurochemistry.
Fluoxetine: a review on evidence based medicine

PubMed Central

Rossi, Andrea; Barraco, Alessandra; Donda, Pietro

2004-01-01

Background Fluoxetine was the first molecule of a new generation of antidepressants, the Selective Serotonin Re-uptake Inhibitors (SSRIs). It is recurrently the paradigm for the development of any new therapy in the treatment of depression. Many controlled studies and meta-analyses were performed on Fluoxetine, to improve the understanding of its real impact in the psychiatric area. The main objective of this review is to assess the quality and the results reported in the meta-analyses published on Fluoxetine. Methods Published articles on Medline, Embase and Cochrane databases reporting meta-analyses were used as data sources for this review. Articles found in the searches were reviewed by 2 independent authors, to assess if these were original meta-analyses. Only data belonging to the most recent and comprehensive meta-analytic studies were included in this review. Results Data, based on a group of 9087 patients, who were included in 87 different randomized clinical trials, confirms that fluoxetine is safe and effective in the treatment of depression from the first week of therapy. Fluoxetine's main advantage over previously available antidepressants (TCAs) was its favorable safety profile, that reduced the incidence of early drop-outs and improved patient's compliance, associated with a comparable efficacy on depressive symptoms. In these patients, Fluoxetine has proven to be more effective than placebo from the first week of therapy. Fluoxetine has shown to be safe and effective in the elderly population, as well as during pregnancy. Furthermore, it was not associated with an increased risk of suicide in the overall evaluation of controlled clinical trials. The meta-analysis available on the use of Fluoxetine in the treatment of bulimia nervosa shows that the drug is as effective as other agents with fewer patients dropping out of treatment. Fluoxetine has demonstrated to be as effective as chlomipramine in the treatment of Obsessive-Compulsive-Disorder (OCD
Sequential treatment with fluoxetine and relapse--prevention CBT to improve outcomes in pediatric depression.

PubMed

Kennard, Betsy D; Emslie, Graham J; Mayes, Taryn L; Nakonezny, Paul A; Jones, Jessica M; Foxwell, Aleksandra A; King, Jessica

2014-10-01

The authors evaluated a sequential treatment strategy of fluoxetine and relapse-prevention cognitive-behavioral therapy (CBT) to determine effects on remission and relapse in youths with major depressive disorder. Youths 8-17 years of age with major depression were treated openly with fluoxetine for 6 weeks. Those with an adequate response (defined as a reduction of 50% or more on the Children's Depression Rating Scale-Revised [CDRS-R]) were randomly assigned to receive continued medication management alone or continued medication management plus CBT for an additional 6 months. The CBT was modified to address residual symptoms and was supplemented by well-being therapy. Primary outcome measures were time to remission (with remission defined as a CDRS-R score of 28 or less) and rate of relapse (with relapse defined as either a CDRS-R score of 40 or more with a history of 2 weeks of symptom worsening, or clinical deterioration). Of the 200 participants enrolled in acute-phase treatment, 144 were assigned to continuation treatment with medication management alone (N=69) or medication management plus CBT (N=75). During the 30-week continuation treatment period, time to remission did not differ significantly between treatment groups (hazard ratio=1.26, 95% CI=0.87, 1.82). However, the medication management plus CBT group had a significantly lower risk of relapse than the medication management only group (hazard ratio=0.31, 95% CI=0.13, 0.75). The estimated probability of relapse by week 30 was lower with medication management plus CBT than with medication management only (9% compared with 26.5%). Continuation-phase relapse-prevention CBT was effective in reducing the risk of relapse but not in accelerating time to remission in children and adolescents with major depressive disorder.
Fluoxetine and vitamin C synergistically inhibits blood-spinal cord barrier disruption and improves functional recovery after spinal cord injury.

PubMed

Lee, Jee Y; Choi, Hae Y; Yune, Tae Y

2016-10-01

Recently we reported that fluoxetine (10 mg/kg) improves functional recovery by attenuating blood spinal cord barrier (BSCB) disruption after spinal cord injury (SCI). Here we investigated whether a low-dose of fluoxetine (1 mg/kg) and vitamin C (100 mg/kg), separately not possessing any protective effect, prevents BSCB disruption and improves functional recovery when combined. After a moderate contusion injury at T9 in rat, a low-dose of fluoxetine and vitamin C, or the combination of both was administered intraperitoneally immediately after SCI and further treated once a day for 14 d. Co-treatment with fluoxetine and vitamin C significantly attenuated BSCB permeability at 1 d after SCI. When only fluoxetine or vitamin C was treated after injury, however, there was no effect on BSCB disruption. Co-treatment with fluoxetine and vitamin C also significantly inhibited the expression and activation of MMP-9 at 8 h and 1 d after injury, respectively, and the infiltration of neutrophils (at 1 d) and macrophages (at 5 d) and the expression of inflammatory mediators (at 2 h, 6 h, 8 h or 24 h after injury) were significantly inhibited by co-treatment with fluoxetine and vitamin C. Furthermore, the combination of fluoxetine and vitamin C attenuated apoptotic cell death at 1 d and 5 d and improved locomotor function at 5 weeks after SCI. These results demonstrate the synergistic effect combination of low-dose fluoxetine and vitamin C on BSCB disruption after SCI and furthermore support the effectiveness of the combination treatment regimen for the management of acute SCI. Copyright © 2016 Elsevier Ltd. All rights reserved.
Dysfunctional Attitudes Scale Perfectionism: A Predictor and Partial Mediator of Acute Treatment Outcome among Clinically Depressed Adolescents

ERIC Educational Resources Information Center

Jacobs, Rachel H.; Silva, Susan G.; Reinecke, Mark A.; Curry, John F.; Ginsburg, Golda S.; Kratochvil, Christopher J.; March, John S.

2009-01-01

The effect of perfectionism on acute treatment outcomes was explored in a randomized controlled trial of 439 clinically depressed adolescents (12-17 years of age) enrolled in the Treatment for Adolescents with Depression Study (TADS) who received cognitive behavior therapy (CBT), fluoxetine, a combination of CBT and FLX, or pill placebo. Measures…
Homeopathic Individualized Q-Potencies versus Fluoxetine for Moderate to Severe Depression: Double-Blind, Randomized Non-Inferiority Trial

PubMed Central

Adler, U. C.; Paiva, N. M. P.; Cesar, A. T.; Adler, M. S.; Molina, A.; Padula, A. E.; Calil, H. M.

2011-01-01

Homeopathy is a complementary and integrative medicine used in depression, The aim of this study is to investigate the non-inferiority and tolerability of individualized homeopathic medicines [Quinquagintamillesmial (Q-potencies)] in acute depression, using fluoxetine as active control. Ninety-one outpatients with moderate to severe depression were assigned to receive an individualized homeopathic medicine or fluoxetine 20 mg day−1 (up to 40 mg day−1) in a prospective, randomized, double-blind double-dummy 8-week, single-center trial. Primary efficacy measure was the analysis of the mean change in the Montgomery & Åsberg Depression Rating Scale (MADRS) depression scores, using a non-inferiority test with margin of 1.45. Secondary efficacy outcomes were response and remission rates. Tolerability was assessed with the side effect rating scale of the Scandinavian Society of Psychopharmacology. Mean MADRS scores differences were not significant at the 4th (P = .654) and 8th weeks (P = .965) of treatment. Non-inferiority of homeopathy was indicated because the upper limit of the confidence interval (CI) for mean difference in MADRS change was less than the non-inferiority margin: mean differences (homeopathy-fluoxetine) were −3.04 (95% CI −6.95, 0.86) and −2.4 (95% CI −6.05, 0.77) at 4th and 8th week, respectively. There were no significant differences between the percentages of response or remission rates in both groups. Tolerability: there were no significant differences between the side effects rates, although a higher percentage of patients treated with fluoxetine reported troublesome side effects and there was a trend toward greater treatment interruption for adverse effects in the fluoxetine group. This study illustrates the feasibility of randomized controlled double-blind trials of homeopathy in depression and indicates the non-inferiority of individualized homeopathic Q-potencies as compared to fluoxetine in acute treatment of outpatients
Chronic treatment with fluoxetine prevents the return of extinguished auditory-cued conditioned fear.

PubMed

Deschaux, Olivier; Spennato, Guillaume; Moreau, Jean-Luc; Garcia, René

2011-05-01

We have recently shown that post-extinction exposure of rats to a sub-threshold reminder shock can reactivate extinguished context-related freezing and found that chronic treatment with fluoxetine before fear extinction prevents this phenomenon. In the present study, we examined whether these findings would be confirmed with auditory fear conditioning. Rats were initially submitted to a session of five tone-shock pairings with either a 0.7- or 0.1-mA shock and underwent, 3 days later, a session of 20 tone-alone trials. At the beginning of this latter session, we observed cue-conditioned freezing in rats that received the strong, but not the weak, shock. At the end, both groups (strong and weak shocks) displayed similar low levels of freezing, indicating fear extinction in rats exposed to the strong shock. These rats exhibited again high levels of cue-evoked freezing when exposed to three tone-shock pairings with 0.1-mA shock. This reemergence of cue-conditioned fear was completely abolished by chronic (over a 21-day period) fluoxetine treatment which spared, when administered before the initial fear conditioning, the original tone-shock association. These data extend our previous findings and suggest that chronic fluoxetine treatment favor extinction memory by dampening the reactivation of the original tone-shock association.
Fluoxetine protects against IL-1β-induced neuronal apoptosis via downregulation of p53.

PubMed

Shan, Han; Bian, Yaqi; Shu, Zhaoma; Zhang, Linxia; Zhu, Jialei; Ding, Jianhua; Lu, Ming; Xiao, Ming; Hu, Gang

2016-08-01

Fluoxetine, a selective serotonin reuptake inhibitor, exerts neuroprotective effects in a variety of neurological diseases including stroke, but the underlying mechanism remains obscure. In the present study, we addressed the molecular events in fluoxetine against ischemia/reperfusion-induced acute neuronal injury and inflammation-induced neuronal apoptosis. We showed that treatment of fluoxetine (40 mg/kg, i.p.) with twice injections at 1 h and 12 h after transient middle cerebral artery occlusion (tMCAO) respectively alleviated neurological deficits and neuronal apoptosis in a mouse ischemic stroke model, accompanied by inhibiting interleukin-1β (IL-1β), Bax and p53 expression and upregulating anti-apoptotic protein Bcl-2 level. We next mimicked neuroinflammation in ischemic stroke with IL-1β in primary cultured cortical neurons and found that pretreatment with fluoxetine (1 μM) prevented IL-1β-induced neuronal apoptosis and upregulation of p53 expression. Furthermore, we demonstrated that p53 overexpression in N2a cell line abolished the anti-apoptotic effect of fluoxetine, indicating that p53 downregulation is required for the protective role of fluoxetine in IL-1β-induced neuronal apoptosis. Fluoxetine downregulating p53 expression could be mimicked by SB203580, a specific inhibitor of p38, but blocked by anisomycin, a p38 activator. Collectively, our findings have revealed that fluoxetine protects against IL-1β-induced neuronal apoptosis via p38-p53 dependent pathway, which give us an insight into the potential of fluoxetine in terms of opening up novel therapeutic avenues for neurological diseases including stroke. Copyright © 2016 Elsevier Ltd. All rights reserved.
Chronic treatment with fluoxetine and sertraline prevents forced swimming test-induced hypercontractility of rat detrusor muscle.

PubMed

Bilge, Sirri; Bozkurt, Ayhan; Bas, Duygu B; Aksoz, Elif; Savli, Evren; Ilkaya, Fatih; Kesim, Yuksel

2008-01-01

Serotonin (5-hydroxytryptamine, 5-HT) reuptake inhibitors represent important targets for the development of new treatments for detrusor overactivity and urinary incontinence. The present study was undertaken to investigate the effects of the forced swimming test (FST) on the contractile response of isolated rat detrusor muscle and to examine the effects of in vivo treatments of fluoxetine and sertraline on altered detrusor muscle contractility. Fluoxetine (20 mg/kg ip) and sertraline (10 mg/kg ip) were administered once a day for 14 days. Rats were exposed to the FST on the 15th day. After the test, detrusor muscles were removed and placed in organ baths, and the contraction responses induced by carbachol, potassium chloride (KCl) and electrical field stimulation (EFS) were recorded. The contractile responses of detrusor muscle strips to carbachol and electrical field stimulation were found to be increased at all carbachol doses and frequencies, respectively. FST also increased the contractile responses to KCl, which is used to test the differences in postreceptor-mediated contractions. The hypercontractile responses of detrusor strips to carbachol, EFS and KCl were abolished by treatment with both fluoxetine and sertraline. These treatments also decreased the immobility duration in the FST consistent with an antidepressant-like effect in this test. The results of this study provide the first evidence that FST increases contractility of the rat detrusor muscle, and this hypercontractility was abolished by chronic treatments of fluoxetine and sertraline at antidepressant doses by decreasing the postreceptor-mediated events.
Rapsyn congenital myasthenic syndrome worsened by fluoxetine.

PubMed

Visser, Amy C; Laughlin, Ruple S; Litchy, William J; Benarroch, Eduardo E; Milone, Margherita

2017-01-01

Fluoxetine is a selective serotonin reuptake inhibitor and long-lived open channel blocker of the acetylcholine receptor, often used in the treatment of slow-channel congenital myasthenic syndromes (CMS). We report a 42-year-old woman who had a history of episodic limb weakness that worsened after initiation of fluoxetine for treatment of depression. Genetic testing for CMS revealed a homozygous pathogenic mutation in the rapsyn (RAPSN) gene (p.Asn88Lys). Electrodiagnostic testing was performed before and 1 month after discontinuation of fluoxetine. The 2 Hz repetitive nerve stimulation of the fibular and spinal accessory nerves showed a baseline decrement of 36% and 14%, respectively. One month after discontinuing fluoxetine, the spinal accessory nerve decrement was no longer present, and the decrement in the fibular nerve was improved at 17%. This case demonstrates worsening of both clinical and electrophysiologic findings in a patient with CMS secondary to a RAPSN mutation treated with fluoxetine. Muscle Nerve 55: 131-135, 2017. © 2016 Wiley Periodicals, Inc.
Changes of cytosolic calcium and contractility of young rat vas deferens by acute treatment with amphetamine, fluoxetine or sibutramine.

PubMed

Jurkiewicz, Neide Hyppolito; da Silva Júnior, Edilson Dantas; de Souza, Bruno Palmieri; Ferreira Verde, Luciana; Drawanz Pereira, Janaina; Mendes Sobrinho, Cairo; Soubhi Smaili, Soraya; Caricati-Neto, Afonso; Miranda-Ferreira, Regiane; Jurkiewicz, Aron

2012-09-15

Previous studies conducted in our laboratory indicated that administration of amphetamine, fluoxetine or sibutramine affects the sympathetic nervous system of the rat vas deferens. Therefore, our goal was to verify the role of calcium in vasa deferentia from young rats pretreated with a single dose of these drugs. Young 40-day-old male Wistar rats were pretreated with amphetamine 3 mg/kg, fluoxetine 10 mg/kg or sibutramine 6 mg/kg for 4 h before the experiments. CaCl(2) (10 mM) was used to induce contraction through time-effect curves in calcium-free solution to measure phasic and tonic components. We also evaluated the calcium-induced fluorescence of vas deferens cut into thin slices. In rats pretreated with amphetamine, we found an increase of the tonic contraction component which was reduced by verapamil. The phasic and tonic responses were increased in the group treated with fluoxetine, but only the tonic response was more sensitive to the antagonism by verapamil. The group treated with sibutramine showed an increase of phasic response whereas the tonic component was decreased. In this group an increase of the affinity for verapamil antagonism was found. In the calcium fluorescence study it was observed that the group treated with amphetamine, fluoxetine or sibutramine showed higher basal Ca(2+) fluorescence after stimulus with KCl (70 mM), noradrenaline (10(-4)M) or acetylcholine (10(-4)M). In all pretreated groups the calcium fluorescence was diminished by nifedipine 10(-7)M. Therefore, the pretreatment with amphetamine, fluoxetine or sibutramine seems to affect the calcium contractility and homeostasis in young rat vas deferens. Copyright © 2012 Elsevier B.V. All rights reserved.
Initial Steps to inform selection of continuation cognitive therapy or fluoxetine for higher risk responders to cognitive therapy for recurrent major depressive disorder.

PubMed

Vittengl, Jeffrey R; Anna Clark, Lee; Thase, Michael E; Jarrett, Robin B

2017-07-01

Responders to acute-phase cognitive therapy (A-CT) for major depressive disorder (MDD) often relapse or recur, but continuation-phase cognitive therapy (C-CT) or fluoxetine reduces risks for some patients. We tested composite moderators of C-CT versus fluoxetine's preventive effects to inform continuation treatment selection. Responders to A-CT for MDD judged to be at higher risk for relapse due to unstable or partial remission (N=172) were randomized to 8 months of C-CT or fluoxetine with clinical management and assessed, free from protocol treatment, for 24 additional months. Pre-continuation-treatment characteristics that in survival analyses moderated treatments' effects on relapse over 8 months of continuation-phase treatment (residual symptoms and negative temperament) and on relapse/recurrence over the full observation period's 32 months (residual symptoms and age) were combined to estimate the potential advantage of C-CT versus fluoxetine for individual patients. Assigning patients to optimal continuation treatment (i.e., to C-CT or fluoxetine, depending on patients' pre-continuation-treatment characteristics) resulted in absolute reduction of relapse or recurrence risk by 16-21% compared to the other non-optimal treatment. Although these novel results require replication before clinical application, selecting optimal continuation treatment (i.e., personalizing treatment) for higher risk A-CT responders may decrease risks of MDD relapse and recurrence substantively. Copyright © 2017 Elsevier Ireland Ltd. All rights reserved.
Absorption of Transdermal Fluoxetine Compounded in a Lipoderm Base Compared to Oral Fluoxetine in Client-owned Cats.

PubMed

Eichstadt, Lauren R; Corriveau, Lorraine A; Moore, George E; Knipp, Gregory T; Cooper, Bruce R; Gwin, Wilson E

2017-01-01

The objective of this study was to compare serum concentrations of transdermal fluoxetine compounded in Lipoderm base versus commercially available oral fluoxetine tablets. Sixteen clinically healthy, client-owned cats that were at least one year of age were enrolled. Cats weighed between three and seven kilograms, had no comorbidities, and were behavior medication naïve. Cats were recruited from January 2016 through April 2016. Eight cats were assigned to each medication group based on owner preference. The cats received either oral (1 mg/kg) or transdermal (5 mg/kg; maximum 25 mg daily) fluoxetine compounded in a transdermal base (PCCA Lipoderm), administered daily for 60 days. Serum levels of fluoxetine and norfluoxetine were assessed as a surrogate for relative efficacy. Serum was collected and analyzed by high-performance liquid chromatography-mass spectrometry/mass spectrometry at baseline and days 5, 10, 30, 45, and 60 post-drug start. Adverse effects were monitored during physical exams, speaking with owners, and laboratory analysis of liver function tests at baseline and days 5, 30, and 60 post-drug start. Serum fluoxetine concentrations significantly differed between the treatment groups at days 45 and 60 post-drug start. Norfluoxetine concentrations significantly differed at days 30, 45, and 60 post-drug start. Blood concentrations of fluoxetine and norfluoxetine significantly differed between oral and transdermal routes after 30 days of treatment. Oral fluoxetine concentrations were consistently higher. Transdermal fluoxetine appeared to be well-tolerated, but a lack of knowledge regarding effective blood levels makes it unclear if a clinical effective response would be obtained at the blood concentrations achieved. Copyright© by International Journal of Pharmaceutical Compounding, Inc.

Strain-specific outcomes of repeated social defeat and chronic fluoxetine treatment in the mouse.

PubMed

Razzoli, Maria; Carboni, Lucia; Andreoli, Michela; Michielin, Francesca; Ballottari, Alice; Arban, Roberto

2011-01-01

Social stress is a risk factor for affective disorders in vulnerable individuals. Although the biological nature of stress susceptibility/resilience remains to be elucidated, genetic variation is considered amongst the principal contributors to brain disorders. Furthermore, genetic predisposition may be determinant for the therapeutic outcome, as proposed for antidepressant treatments. In the present studies we compared the inherently diverse genetic backgrounds of 2 mouse strains by assessing the efficacy of a chronic antidepressant treatment in a repeated social stress procedure. C57BL/6J and BalbC mice underwent 10-day social defeats followed by 28-day fluoxetine treatment (10 mg/kg/mL, p.o.). In C57BL/6J, most of the social defeat-induced changes were of metabolic nature including persistently altered feed efficiency and decreased abdominal fat stores that were ameliorated by fluoxetine. BalbC mouse behavior was persistently affected by social defeat both in the social avoidance and the forced swim tests, and in either procedure it was restored by chronic fluoxetine, whereas their endocrine parameters were mostly unaffected. The highlighted strain-specific responsivity to the metabolic and behavioral consequences of social defeat and to the chronic antidepressant treatment offers a promising research tool to further explore the underlying neural mechanisms and genetic basis of stress susceptibility and treatment response. Copyright © 2010 Elsevier Inc. All rights reserved.
Acute and chronic anxiogenic-like response to fluoxetine in rats in the elevated plus-maze: modulation by stressful handling.

PubMed

Robert, Gabriel; Drapier, Dominique; Bentué-Ferrer, Danièle; Renault, Alain; Reymann, Jean-Michel

2011-07-07

While antidepressants are widely prescribed to humans for the treatment of anxiety, the results achieved with animal anxiety models are conflicting. The experimental procedure and the prior test history of the animals are critical parameters that are largely susceptible to influence the results and their interpretation. We compared the effect of 5mg fluoxetine administered to six groups of rats subjected to the psychopharmacological test of the elevated plus-maze, under experimental conditions designed to demonstrate the effect of handling and one daily injection on the response to fluoxetine. The results show that for animals with the same recent experience, fluoxetine, when administered once or over a period of 15 days, induces anxiogenic-like behaviour. On the other hand, our results also show that stressful handling has an anxiolytic-like effect modulating the anxiogenic-like effect of fluoxetine, without eliminating it altogether. Copyright © 2011 Elsevier B.V. All rights reserved.
Effects of fluoxetine on changes of pain sensitivity in chronic stress model rats.

PubMed

Lian, Yan-Na; Chang, Jin-Long; Lu, Qi; Wang, Yi; Zhang, Ying; Zhang, Feng-Min

2017-06-09

Exposure to stress could facilitate or inhibit pain responses (stress-induced hyperalgesia or hypoalgesia, respectively). Fluoxetine is a selective serotonin (5-HT) reuptake inhibitor antidepressant. There have been contradictory reports on whether fluoxetine produces antinociceptive effects. The purpose of this study was to elucidate changes in pain sensitivity after chronic stress exposure, and the effects of fluoxetine on these changes. We measured thermal, mechanical, and formalin-induced acute and inflammatory pain by using the tail-flick, von Frey, and formalin tests respectively. The results showed that rats exposed to chronic stress exhibited thermal and formalin-induced acute and inflammatory hypoalgesia and transient mechanical hyperalgesia. Furthermore, fluoxetine promoted hypoalgesia in thermal and inflammatory pain and induced mechanical hyperalgesia. Our results indicate that the 5-HT system could be involved in hypoalgesia of thermal and inflammatory pain and induce transient mechanical hyperalgesia after stress exposure. Copyright © 2017 Elsevier B.V. All rights reserved.
Assessing the environmental hazard of individual and combined pharmaceuticals: acute and chronic toxicity of fluoxetine and propranolol in the crustacean Daphnia magna.

PubMed

Varano, Valentina; Fabbri, Elena; Pasteris, Andrea

2017-08-01

Pharmaceuticals are widespread emerging contaminants and, like all pollutants, are present in combination with others in the ecosystems. The aim of the present work was to evaluate the toxic response of the crustacean Daphnia magna exposed to individual and combined pharmaceuticals. Fluoxetine, a selective serotonin re-uptake inhibitor widely prescribed as antidepressant, and propranolol, a non-selective β-adrenergic receptor-blocking agent used to treat hypertension, were tested. Several experimental trials of an acute immobilization test and a chronic reproduction test were performed. Single chemicals were first tested separately. Toxicity of binary mixtures was then assessed using a fixed ratio experimental design. Five concentrations and 5 percentages of each substance in the mixture (0, 25, 50, 75, and 100%) were tested. The MIXTOX model was applied to analyze the experimental results. This tool is a stepwise statistical procedure that evaluates if and how observed data deviate from a reference model, either concentration addition (CA) or independent action (IA), and provides significance testing for synergism, antagonism, or more complex interactions. Acute EC50 values ranged from 6.4 to 7.8 mg/L for propranolol and from 6.4 to 9.1 mg/L for fluoxetine. Chronic EC50 values ranged from 0.59 to 1.00 mg/L for propranolol and from 0.23 to 0.24 mg/L for fluoxetine. Results showed a significant antagonism between chemicals in both the acute and the chronic mixture tests when CA was adopted as the reference model, while absence of interactive effects when IA was used.
Fluoxetine Facilitates Fear Extinction Through Amygdala Endocannabinoids

PubMed Central

Gunduz-Cinar, Ozge; Flynn, Shaun; Brockway, Emma; Kaugars, Katherine; Baldi, Rita; Ramikie, Teniel S; Cinar, Resat; Kunos, George; Patel, Sachin; Holmes, Andrew

2016-01-01

Pharmacologically elevating brain endocannabinoids (eCBs) share anxiolytic and fear extinction-facilitating properties with classical therapeutics, including the selective serotonin reuptake inhibitor, fluoxetine. There are also known functional interactions between the eCB and serotonin systems and preliminary evidence that antidepressants cause alterations in brain eCBs. However, the potential role of eCBs in mediating the facilitatory effects of fluoxetine on fear extinction has not been established. Here, to test for a possible mechanistic contribution of eCBs to fluoxetine's proextinction effects, we integrated biochemical, electrophysiological, pharmacological, and behavioral techniques, using the extinction-impaired 129S1/Sv1mJ mouse strain. Chronic fluoxetine treatment produced a significant and selective increase in levels of anandamide in the BLA, and an associated decrease in activity of the anandamide-catabolizing enzyme, fatty acid amide hydrolase. Slice electrophysiological recordings showed that fluoxetine-induced increases in anandamide were associated with the amplification of eCB-mediated tonic constraint of inhibitory, but not excitatory, transmission in the BLA. Behaviorally, chronic fluoxetine facilitated extinction retrieval in a manner that was prevented by systemic or BLA-specific blockade of CB1 receptors. In contrast to fluoxetine, citalopram treatment did not increase BLA eCBs or facilitate extinction. Taken together, these findings reveal a novel, obligatory role for amygdala eCBs in the proextinction effects of a major pharmacotherapy for trauma- and stressor-related disorders and anxiety disorders. PMID:26514583
Fluoxetine Facilitates Fear Extinction Through Amygdala Endocannabinoids.

PubMed

Gunduz-Cinar, Ozge; Flynn, Shaun; Brockway, Emma; Kaugars, Katherine; Baldi, Rita; Ramikie, Teniel S; Cinar, Resat; Kunos, George; Patel, Sachin; Holmes, Andrew

2016-05-01

Pharmacologically elevating brain endocannabinoids (eCBs) share anxiolytic and fear extinction-facilitating properties with classical therapeutics, including the selective serotonin reuptake inhibitor, fluoxetine. There are also known functional interactions between the eCB and serotonin systems and preliminary evidence that antidepressants cause alterations in brain eCBs. However, the potential role of eCBs in mediating the facilitatory effects of fluoxetine on fear extinction has not been established. Here, to test for a possible mechanistic contribution of eCBs to fluoxetine's proextinction effects, we integrated biochemical, electrophysiological, pharmacological, and behavioral techniques, using the extinction-impaired 129S1/Sv1mJ mouse strain. Chronic fluoxetine treatment produced a significant and selective increase in levels of anandamide in the BLA, and an associated decrease in activity of the anandamide-catabolizing enzyme, fatty acid amide hydrolase. Slice electrophysiological recordings showed that fluoxetine-induced increases in anandamide were associated with the amplification of eCB-mediated tonic constraint of inhibitory, but not excitatory, transmission in the BLA. Behaviorally, chronic fluoxetine facilitated extinction retrieval in a manner that was prevented by systemic or BLA-specific blockade of CB1 receptors. In contrast to fluoxetine, citalopram treatment did not increase BLA eCBs or facilitate extinction. Taken together, these findings reveal a novel, obligatory role for amygdala eCBs in the proextinction effects of a major pharmacotherapy for trauma- and stressor-related disorders and anxiety disorders.
Fluoxetine increases suicide ideation less than placebo during treatment of adults with minor depressive disorder.

PubMed

Garlow, Steven J; Kinkead, Becky; Thase, Michael E; Judd, Lewis L; Rush, A John; Yonkers, Kimberly A; Kupfer, David J; Frank, Ellen; Schettler, Pamela J; Rapaport, Mark Hyman

2013-09-01

Some reports suggest an increase in suicide ideations and behaviors in patients treated with antidepressants. This is an analysis of the impact of fluoxetine on suicide ideations in outpatients with minor depressive disorder. Research subjects were adult outpatients with minor depressive disorder (N = 162), who received fluoxetine or placebo in a prospective, 12-week, double-blind randomized trial. The research participants were evaluated weekly with standard rating scales that included four suicide-related items: item 3 of the Hamilton Rating Scale for Depression (HRSD), item 18 of Inventory of Depressive Symptomatology (IDS-C), and items 15 and 59 of the Hopkins Symptom Checklist (SCL-90). Clinically significant intensification of suicide ideation was defined as an increase of ≥2 points on any of these items. Overall 60/162 subjects (37%) had an increase of ≥1 point during treatment and 17/162 (10.5%) of ≥2 points on at least one suicide item, with 12/81 (14.8%) placebo and 5/81 (6.2%) fluoxetine-treated subjects having a ≥2 point gain. Of the study participants with baseline suicide ideation, 9/22 (40.9%) placebo and 3/24 (12.5%) fluoxetine treated had ≥2 point increase (p = 0.04). Survival analysis revealed that subjects on placebo were significantly more likely (p = 0.050) to experience a ≥2 point increase on one or more item, a difference that emerged early and continued throughout the 12-week trial. Compared to placebo, fluoxetine was not associated with a clinically significant increase in suicide ideation among adults with minor depressive disorder during 12 weeks of treatment. Copyright © 2013 Elsevier Ltd. All rights reserved.
Fluoxetine Increases Suicide Ideation Less than Placebo During Treatment of Adults with Minor Depressive Disorder

PubMed Central

Garlow, Steven J.; Kinkead, Becky; Thase, Michael E.; Judd, Lewis L.; Rush, A. John; Yonkers, Kimberly A.; Kupfer, David J.; Frank, Ellen; Schettler, Pamela J.; Rapaport, Mark Hyman

2013-01-01

Objective Some reports suggest an increase in suicide ideations and behaviors in patients treated with antidepressants. This is an analysis of the impact of fluoxetine on suicide ideations in outpatients with Minor Depressive Disorder. Methods Research subjects were adult outpatients with Minor Depressive Disorder (N=162), who received fluoxetine or placebo in a prospective, 12-week, double blind randomized trial. The research participants were evaluated weekly with standard rating scales that included 4 suicide-related items; item 3 of the Hamilton Rating Scale for Depression (HRSD), item 18 of Inventory of Depressive Symptomatology (IDS-C), and items 15 and 59 of the Hopkins Symptom Checklist (SCL-90). Clinically significant intensification of suicide ideation was defined as an increase of ≥2 on any of these items. Results Overall 60/162 subjects (37%) had an increase of ≥1 point during treatment and 17/162 (10.5%) of ≥2 points on at least one suicide item, with 12/81 (14.8%) placebo and 5/81 (6.2%) fluoxetine treated subjects having a ≥2 point gain. Of the study participants with baseline suicide ideation, 9/22 (40.9%) placebo and 3/24 (12.5%) fluoxetine treated had ≥2 point increase (p=0.04). Survival analysis revealed that subjects on placebo were significantly more likely (p=0.050) to experience a ≥2 point increase on one or more item, a difference that emerged early and continued throughout the 12-week trial. Conclusions Compared to placebo, fluoxetine was not associated with a clinically significant increase in suicide ideation among adults with Minor Depressive Disorder during 12 weeks of treatment. PMID:23786912
Fluoxetine reverses the behavioral despair induced by neurogenic stress in mice: role of N-methyl-d-aspartate and opioid receptors.

PubMed

Haj-Mirzaian, Arya; Kordjazy, Nastaran; Ostadhadi, Sattar; Amiri, Shayan; Haj-Mirzaian, Arvin; Dehpour, AhmadReza

2016-06-01

Opioid and N-methyl-d-aspartate (NMDA) receptors mediate different effects of fluoxetine. We investigated whether opioid and NMDA receptors are involved in the protective effect of fluoxetine against the behavioral despair induced by acute physical stress in male mice. We used the forced swimming test (FST), tail suspension test (TST), and open-field test (OFT) for behavioral evaluation. We used fluoxetine, naltrexone (opioid receptor antagonist), MK-801 (NMDA receptor antagonist), morphine (opioid receptor agonist), and NMDA (NMDA receptor agonist). Acute foot-shock stress (FSS) significantly induced behavioral despair (depressive-like) and anxiety-like behaviors in tests. Fluoxetine (5 mg/kg) reversed the depressant-like effect of FSS, but it did not alter the locomotion and anxiety-like behavior in animals. Acute administration of subeffective doses of naltrexone (0.3 mg/kg) or MK-801 (0.01 mg/kg) potentiated the antidepressant-like effect of fluoxetine, while subeffective doses of morphine (1 mg/kg) and NMDA (75 mg/kg) abolished this effect of fluoxetine. Also, co-administration of subeffective doses of naltrexone (0.05 mg/kg) and MK-801 (0.003 mg/kg) with fluoxetine (1 mg/kg) induced a significant decrease in the immobility time in FST and TST. Our results showed that opioid and NMDA receptors (alone or in combination) are involved in the antidepressant-like effect of fluoxetine against physical stress.
Fluoxetine Treatment for Prevention of Relapse of Depression in Children and Adolescents: A Double-Blind, Placebo-Controlled Study

ERIC Educational Resources Information Center

Emslie, Graham J.; Heiligenstein, John H.; Hoog, Sharon L.; Wagner, Karen Dineen; Findling, Robert L.; McCracken, James T.; Nilsson, Mary E.; Jacobson, Jennie G.

2004-01-01

Objective: To compare fluoxetine 20 to 60 mg/day with placebo for prevention of relapse of major depressive disorder in children and adolescents who had achieved Children's Depression Rating Scale, Revised scores of [less than or equal to]28 during treatment with fluoxetine 20 to 60 mg. Method: In this 32-week relapse-prevention phase of a…
Fluoxetine ameliorates imbalance of redox homeostasis and inflammation in an acute kidney injury model.

PubMed

Aksu, Ugur; Guner, Ibrahim; Yaman, Onur M; Erman, Hayriye; Uzun, Duygu; Sengezer-Inceli, Meliha; Sahin, Ahmet; Yelmen, Nermin; Gelisgen, Remisa; Uzun, Hafize; Sahin, Gulderen

2014-12-01

Ischemia-reperfusion (IR) has been reported to be associated with augmented reactive oxygen radicals and cytokines. Currently, we aimed to examine the influence of fluoxetine, which is already used as a preoperative anxiolytic, in the context of IR induced by occlusion of infrarenal abdominal aorta (60 min of ischemia) and its effects on renal oxidative status, inflammation, renal function, and cellular integrity in reperfusion (120 min post-ischemia). Male rats were randomly assigned as control, IR, and pretreated groups. The pretreated group animals received fluoxetine (20 mg/kg, i.p.) once daily for 3 days. Renal tissue oxidative stress, myeloperoxidase activity, proinflammatory cytokines (tumor necrosis factor-α, interleukin-1β, interleukin-6), histology, and function were assessed. As an anti-inflammatory cytokine, interleukin-10 was also assessed. IR led to a significant increase in lipid hydroperoxide, malondialdehyde, and pro-oxidant antioxidant balance and decrease in superoxide dismutase activity and ferric reducing/antioxidant power level (p < 0.05), but fluoxetine was able to restore these parameters. High concentrations of tumor necrosis factor-α, interleukin-1β, interleukin-6, and myeloperoxidase activity caused by IR were significantly decreased in kidney tissue with fluoxetine. In addition, interleukin-10 levels were high in fluoxetine pretreated group. IR resulted in disrupted cellular integrity, infiltration of tissue with leukocytes, and decreased serum creatinine-urea levels (p < 0.05). Fluoxetine significantly restored impaired redox balance and inflammation parameters of rats subjected to IR to baseline values. This beneficial effect of fluoxetine on redox balance might be addressed to an improvement in renal function.
Effects of antidepressant treatment with rTMS and fluoxetine on brain perfusion in PD.

PubMed

Fregni, F; Ono, C R; Santos, C M; Bermpohl, F; Buchpiguel, C; Barbosa, E R; Marcolin, M A; Pascual-Leone, A; Valente, K D

2006-06-13

Although depression is highly prevalent in Parkinson disease (PD), little is known about the neural correlates associated with depression and antidepressant treatment in PD. To examine the effects of fluoxetine and repetitive transcranial magnetic stimulation (rTMS) on regional cerebral blood flow (rCBF) using SPECT in patients with PD and depression. Twenty-six patients were enrolled into two groups: One received active rTMS and placebo medication and the other sham rTMS and fluoxetine 20 mg/day. Brain SPECT was performed at baseline and after 2 and 8 weeks. Changes in rCBF were compared across timepoints and correlated with clinical scores. In addition, baseline rCBF of these patients was compared with that of 29 healthy, age-matched subjects. At baseline, patients with PD and depression showed significantly lower rCBF in the left prefrontal cortex, posterior cingulate gyrus, left insula, and right parietal cortex when compared with healthy controls. Both treatments induced significant clinical improvement and increases in rCBF in the posterior cingulate gyrus and decreases in rCBF in the right medial frontal gyrus. These changes were significantly correlated to the clinical outcome. Furthermore, the comparison between these two treatments revealed that whereas rTMS treatment was associated with an increased perfusion in the right and left prefrontal cortex, fluoxetine treatment was associated with a relative rCBF increase in the occipital lobe. Depression in patients with Parkinson disease is correlated with a dysfunction of the frontal-limbic network that can be modulated by two different antidepressant therapies.
Mechanism of synergistic action following co-treatment with pramipexole and fluoxetine or sertraline in the forced swimming test in rats.

PubMed

Rogóz, Zofia; Skuza, Grazyna

2006-01-01

The aim of the present study was to examine the effect of combined treatment of male Wistar rats with pramipexole and fluoxetine or sertraline in the forced swimming test. The obtained results showed that co-treatment with pramipexole (0.1 mg/kg) and fluoxetine (10 mg/kg) or sertraline (5 mg/kg) (in doses inactive per se) exhibited antidepressant-like activity in the forced swimming test. Sulpiride (a dopamine D(2/3) receptor antagonist) and WAY 100635 (a 5-HT(1A) receptor antagonist), either being ineffective in the forced swimming test, inhibited the antidepressant-like effect induced by co-administration of pramipexole and fluoxetine or sertraline. However, SCH 23390 (a dopamine D(1) receptor antagonist) only partly did not alter the effect of pramipexole given jointly with antidepressant drugs; on the other hand, S 33084 (a dopamine D(3) receptor antagonist) only partly decreased (in a statistically insignificant manner) that effect. Moreover, progesterone and BD 1047 (a sigma(1) receptor antagonist) counteracted the antidepressant-like effect induced by co-administration of pramipexole and sertraline (but not pramipexole and fluoxetine). In that test, active behavior did not reflect the increases in general activity, since combined administration of pramipexole and fluoxetine or sertraline failed to enhance the locomotor activity of rats. None of the tested drugs (SCH 23390, sulpiride, S 33084, WAY 100635, BD 1047 and progesterone) - alone or in combination with pramipexole and fluoxetine or sertraline - changed locomotor activity. The results described in the present paper indicate that co-administration of pramipexole and fluoxetine or sertraline may induce a more pronounced antidepressive activity than does treatment with pramipexole alone, and that in addition to other mechanisms, dopamine D(2/3) and 5-HT(1A) receptors may contribute to the antidepressant-like activity of pramipexole and fluoxetine or sertraline in the forced swimming test in rats
Fluoxetine vs. placebo for the treatment of recurrent vasovagal syncope with anxiety sensitivity.

PubMed

Flevari, Panayota; Leftheriotis, Dionyssios; Repasos, Evangelos; Katsaras, Dimitrios; Katsimardos, Andreas; Lekakis, John

2017-01-01

The optimal medical therapy of patients with vasovagal syncope (VVS) remains controversial. Fluoxetine is effective against anxiety and panic disorders, while its use has shown promising results for VVS. Anxiety sensitivity is a personality trait observed in a considerable proportion of patients with VVS, associated with predisposition to anxiety and panic disorders. Our aim was to examine whether fluoxetine exerts beneficial effects regarding VVS prevention in the subset of patients with anxiety sensitivity. We assessed 106 patients with typical history of recurrent VVS, without other comorbidities, and a diagnostic, positive head-up tilt test. A psychiatric examination ruled out clinical psychiatric disease. Their psychological, stress-related profile was assessed by the Anxiety Sensitivity Index (ASI) questionnaire, a 16-item questionnaire, assessing fear of anxiety-related sensations, previously studied in VVS. Patients scoring positive for ASI (n = 60, 57% of the population) were randomized in a 2:1 fashion to receive either 10-40 mg fluoxetine daily (n = 40) or placebo (n = 20), and were followed-up for 1 year. A significant difference was observed between patients receiving fluoxetine and those with placebo, regarding the distribution of syncope-free time during the study (P < 0.05). A significant difference was also observed between the two groups regarding presyncopal events and the total number of patients who experienced syncope or presyncope during follow-up. Sensitivity to anxiety is a common personality trait in recurrent VVS. Fluoxetine is superior to placebo against syncope in these patients. This drug may be a first-line pharmacological treatment for this difficult-to-treat group. Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2016. For permissions please email: journals.permissions@oup.com.
Gestational stress and fluoxetine treatment differentially affect plasticity, methylation and serotonin levels in the PFC and hippocampus of rat dams.

PubMed

Gemmel, Mary; Rayen, Ine; van Donkelaar, Eva; Loftus, Tiffany; Steinbusch, Harry W; Kokras, Nikolaos; Dalla, Christina; Pawluski, Jodi L

2016-07-07

Women are more likely to develop depression during childbearing years with up to 20% of women suffering from depression during pregnancy and in the postpartum period. Increased prevalence of depression during the perinatal period has resulted in frequent selective serotonin reuptake inhibitor (SSRI) antidepressant treatment; however the effects of such medications on the maternal brain remain limited. Therefore, the aim of the present study is to investigate the effects of the SSRI medication, fluoxetine, on neurobiological differences in the maternal brain. To model aspects of maternal depression, gestational stress was used. Sprague-Dawley rat dams were exposed to either gestational stress and/or fluoxetine (5mg/kg/day) to form the following four groups: 1. Control+Vehicle, 2. Stress+Vehicle, 3. Control+Fluoxetine, and 4. Stress+Fluoxetine. At weaning maternal brains were collected. Main findings show that gestational stress alone increased synaptophysin and serotonin metabolism in the cingulate cortex2 region of the cortex while fluoxetine treatment after stress normalized these effects. In the hippocampus, fluoxetine treatment, regardless of gestational stress exposure, decreased both global measures of methylation in the dentate gyrus, as measured by Dnmt3a immunoreactivity, as well as serotonin metabolism. No further changes in synaptophysin, PSD-95, or Dnmt3a immunoreactivity were seen in the cortical or hippocampal areas investigated. These findings show that gestational stress and SSRI medication affect the neurobiology of the maternal brain in a region-specific manner. This work adds to a much needed area of research aimed at understanding neurobiological changes associated with maternal depression and the role of SSRI treatment in altering these changes in the female brain. Copyright © 2016 IBRO. Published by Elsevier Ltd. All rights reserved.
Factors influencing fluoxetine-induced sexual dysfunction in female rats

PubMed Central

Adams, Sarah; Heckard, Danyeal; Hassell, James; Uphouse, Lynda

2012-01-01

Treatment with selective serotonin reuptake inhibitors, such as fluoxetine, produces sexual side effects with low sexual desire being the most prevalent effect in females. In few studies have preclinical models for such antidepressant-induced sexual dysfunction been fruitful. In the current manuscript, the effects of fluoxetine on multiple measures of female sexual motivation and sexual receptivity were examined. Ovariectomized, Fischer rats were primed with 10 μg estradiol benzoate and 500 μg progesterone. Partner preference, active investigation of the male, and measures of sexual behavior were examined after injection with 15 mg/kg fluoxetine. Factors (pretesting for sexual behavior, size of the test arena, non-contact time with a male) that differ among experiments designed to study antidepressant-induced female rat sexual dysfunction were studied. The male preference ratio was not affected by fluoxetine treatment but active investigation of the male was reduced; lordosis behavior was inhibited and pretesting for sexual receptivity amplified fluoxetine's inhibition; size of the testing arena or non-contact experience with the male had no effect. Regardless of test condition, when given the opportunity to escape from the male, fluoxetine-treated females displayed escape behavior. Measures of male preference and active investigation, but not lordosis behavior, appeared to be affected by fluoxetine's impact on activity. The collective data provided a behavioral profile of fluoxetine-induced sexual dysfunction. These findings reinforce the value of multiple measures when attempting to model antidepressant-induced female sexual dysfunction. PMID:22835821
Effectiveness and cost-effectiveness of antidepressant treatment in primary health care: a six-month randomised study comparing fluoxetine to imipramine.

PubMed

Serrano-Blanco, A; Gabarron, E; Garcia-Bayo, I; Soler-Vila, M; Caramés, E; Peñarrubia-Maria, M T; Pinto-Meza, A; Haro, J M

2006-04-01

Over the past decade, studies of the effectiveness of pharmacological treatment for depression have often been based on research designs intended to measure efficacy, and for this reason the results are of limited generalizability. Research is needed comparing the clinical and economic outcomes of antidepressants in day-to-day clinical practice. A six-month randomised prospective naturalistic study comparing fluoxetine to imipramine carried out in three primary care health centres. Outcome measures were the Montgomery Asberg Depression Rating Scale (MADRS), direct costs, indirect costs and total costs. Subjects were evaluated at the beginning of treatment and at one, three and six months thereafter. Of the 103 patients, 38.8% (n = 40) were diagnosed with major depressive disorder, 14.6% (n = 15) with dysthymic disorder, and 46.6% (n = 48) with depressive disorder not otherwise specified. Patients with major depressive disorder or dysthymic disorder achieved similar clinical improvement in both treatment groups (mean MADRS ratings decrease in major depressive disorder from baseline to 6 months of 18.3 for imipramine and 18.8 for fluoxetine). For patients with major depressive disorder and dysthymic disorder, the imipramine group had fewer treatment-associated costs (imipramine 469.66 Euro versus fluoxetine 1,585.93 Euro in major depressive disorder, p < 0.05; imipramine 175.39 Euro versus fluoxetine 2,929.36 Euro in dysthymic disorder, p < 0.05). The group with depressive disorder not otherwise specified did not experience statistically significant differences in clinical and costs outcomes between treatment groups. Exclusion criteria, participating physicians may not represent GPs. In a primary care context, imipramine may represent a more cost-effective treatment option than fluoxetine for treating major depressive disorder or dysthymic disorder. There were no differences in cost-effectiveness in the treatment of depressive disorder not otherwise specified.
Altered CB receptor-signaling in prefrontal cortex from an animal model of depression is reversed by chronic fluoxetine.

PubMed

Rodríguez-Gaztelumendi, Antonio; Rojo, M Luisa; Pazos, Angel; Díaz, Alvaro

2009-03-01

Bilateral olfactory bulbectomy in the rat (OBX) induces behavioral, neurochemical, and structural abnormalities similar to those observed in human depression that are normalized after chronic, but not acute, treatment with antidepressants. In our study, OBX animals exhibited significant increases in both CB(1) receptor density ([(3)H]CP55490 binding) and functionality (stimulation of [(35)S]GTPgammaS binding by the cannabinoid (CB) agonist WIN 55212-2) at the prefrontal cortex (PFC). After chronic treatment with fluoxetine (10 mg/kg/day, 14 days, s.c.), OBX-induced hyperactivity in the open-field test was fully abolished. Interestingly, chronic fluoxetine fully reversed the enhanced CB(1)-receptor signaling in PFC observed following OBX. The CB agonist Delta(9)-tetrahydrocannabinol (5 mg/kg, i.p., 1 day) did not produce any behavioral effect in sham-operated animals but returned locomotor activity to control values in OBX rats. As both acute administration of Delta(9)-tetrahydrocannabinol and chronic fluoxetine elicited a similar behavioral effect in the OBX rat, it is not unlikely that the regionally selective enhancement of CB(1) receptor-signaling in the PFC could be related with the altered OBX behavior. Our findings reinforce the utility of this animal model to further investigating the implication of the endocannabinoid system in the modulation of emotional processes and its potential role in the adaptive responses to chronic antidepressants.
Chronic fluoxetine inhibits sexual behavior in the male rat: reversal with oxytocin.

PubMed

Cantor, J M; Binik, Y M; Pfaus, J G

1999-06-01

Selective serotonin reuptake inhibitors, used widely in the treatment of depression, progressively inhibit sexual orgasm in many patients and induce a transient inhibition of sexual desire. We attempted to model the effects of these drugs in sexually experienced male rats during tests of copulation in bilevel chambers. These chambers allow the study of both appetitive and consummatory sexual responses of male rats. Males were treated daily with fluoxetine hydrochloride (0, 1, 5, or 10 mg/kg) and tested for sexual behavior with receptive females at 4-day intervals. Rats were treated with oxytocin (200 ng/kg) or saline after ejaculations had decreased. Fluoxetine decreased ejaculatory responses of male rats in a dose- and time-dependent fashion, but left the copulatory efficiency of the males intact. In contrast, conditioned level changing, a measure of appetitive sexual excitement, was inhibited following acute and chronic treatment with 10 mg/kg, although tolerance may have developed to the effect of 5 mg/kg. Subsequent administration of oxytocin restored the ejaculatory response but not the measure of sexual excitement to baseline levels. The reversal by oxytocin of the fluoxetine-induced deficit in ejaculations is consistent with the hypothesis that serotonin suppresses ejaculatory mechanisms by interrupting the action of oxytocin, which normally accompanies sexual behavior. Co-administration of oxytocin may help to alleviate the predominant sexual side effect of serotonin reuptake blockers.
Perinatal Fluoxetine Exposure Impairs the CO2 Chemoreflex. Implications for Sudden Infant Death Syndrome.

PubMed

Bravo, Karina; Eugenín, Jaime L; Llona, Isabel

2016-09-01

High serotonin levels during pregnancy affect central nervous system development. Whether a commonly used antidepressant such as fluoxetine (a selective serotonin reuptake inhibitor) taken during pregnancy may adversely affect respiratory control in offspring has not been determined. The objective was to determine the effect of prenatal-perinatal fluoxetine exposure on the respiratory neural network in offspring, particularly on central chemoreception. Osmotic minipumps implanted into CF-1 mice on Days 5-7 of pregnancy delivered 7 milligrams per kilogram per day of fluoxetine, achieving plasma levels within the range found in patients. Ventilation was assessed in offspring at postnatal Days 0-40 using head-out body plethysmography. Neuronal activation was evaluated in the raphe nuclei and in the nucleus tractus solitarius by c-Fos immunohistochemistry during normoxic eucapnia and hypercapnia (10% CO2). Respiratory responses to acidosis were evaluated in brainstem slices. Prenatal-perinatal fluoxetine did not affect litter size, birth weight, or the postnatal growth curve. Ventilation under eucapnic normoxic conditions was similar to that of control offspring. Fluoxetine exposure reduced ventilatory responses to hypercapnia at P8-P40 (P < 0.001) but not at P0-P5. At P8, it reduced hypercapnia-induced neuronal activation in raphe nuclei (P < 0.05) and nucleus tractus solitarius (P < 0.01) and the acidosis-induced increase in the respiratory frequency in brainstem slices (P < 0.05). Fluoxetine applied acutely on control slices did not modify their respiratory response to acidosis. We concluded that prenatal-perinatal fluoxetine treatment impairs central respiratory chemoreception during postnatal life. These results are relevant in understanding the pathogenesis of respiratory failures, such as sudden infant death syndrome, associated with brainstem serotonin abnormalities and the failure of respiratory chemoreflexes.

Switching to moclobemide to reverse fluoxetine-induced sexual dysfunction in patients with depression.

PubMed Central

Ramasubbu, R

1999-01-01

OBJECTIVE: To determine the efficacy of substituting moclobemide, a reversible monoamine oxidase-A inhibitor, for fluoxetine to reverse fluoxetine-induced sexual dysfunction in patients with depression. DESIGN: Prospective open trial. SETTING: Outpatient treatment. PARTICIPANTS: Five patients with depressive disorder who experienced sexual side effects during treatment with standard doses of fluoxetine (20 to 40 mg per day). INTERVENTION: Discontinuation of fluoxetine and replacement with moclobemide (300 to 600 mg per day) after a 2-week washout period. OUTCOME MEASURES: Libido, orgasmic function (in women) or erectile and ejaculatory function (in men), and overall improvement in sexual function during a follow-up period of 2 months to 3 years. RESULTS: Among patients receiving fluoxetine questioned about sexual side effects, 4 (1 man and 3 women) had treatment-related diminished libido with poor orgasmic response or partial erectile failure, and 1 female patient had enhanced sexual desire with intense clitoral stimulation. In all patients, sexual disturbances resolved completely after a 2-week washout period and a switch to treatment with moclobemide. Moclobemide was well tolerated. The antidepressant effect of moclobemide was comparable to that of fluoxetine. CONCLUSIONS: Moclobemide may be preferred as a treatment for depression in patients with fluoxetine-induced sexual dysfunction. PMID:9987207
FLUOXETINE INHIBITS OSTEOBLAST DIFFERENTIATION & MINERALIZATION IN FRACTURE HEALING

PubMed Central

Bradaschia-Correa, Vivian; Josephson, Anne M; Mehta, Devan; Mizrahi, Matthew; Neibart, Shane S; Liu, Chao; Kennedy, Oran; Castillo, Alesha B; Egol, Kenneth A; Leucht, Philipp

2016-01-01

Chronic use of selective serotonin reuptake inhibitors (SSRIs) for the treatment of depression has been linked to osteoporosis. In this study, we investigated the effect of chronic SSRI use on fracture healing in two murine models of bone regeneration. First, we performed a comprehensive analysis of endochondral bone healing in a femur fracture model. C57/BL6 mice treated with fluoxetine, the most commonly prescribed SSRI, developed a normal cartilaginous soft-callus at 14 days after fracture and demonstrated a significantly smaller and biomechanically weaker bony hard-callus at 28 days. In order to further dissect the mechanism that resulted in a smaller bony regenerate, we used an intramembranous model of bone healing and revealed that fluoxetine treatment resulted in a significantly smaller bony callus at 7 and 14 days postinjury. In order to test whether the smaller bony regenerate following fluoxetine treatment was caused by an inhibition of osteogenic differentiation and/or mineralization, we employed in vitro experiments, which established that fluoxetine treatment decreases osteogenic differentiation and mineralization and that this effect is serotonin-independent. Finally, in a translational approach, we tested whether cessation of the medication would result in restoration of the regenerative potential. However, histologic and µCT analysis revealed non-union formation in these animals with fibrous tissue interposition within the callus. In conclusion, fluoxetine exerts a direct, inhibitory effect on osteoblast differentiation and mineralization, shown in two disparate murine models of bone repair. Discontinuation of the drug did not result in restoration of the healing potential, but rather led to complete arrest of the repair process. Besides the well-established effect of SSRIs on bone homeostasis, our study provides strong evidence that fluoxetine use negatively impacts fracture healing. PMID:27869327
SET-C versus Fluoxetine in the Treatment of Childhood Social Phobia

ERIC Educational Resources Information Center

Beidel, Deborah C.; Turner, Samuel M.; Ammerman, Robert T.; Sallee, Floyd R.; Crosby, Lori A.; Pathak, Sanjeev

2007-01-01

A study examines the effectiveness of fluoxetine, pill placebo and Social Effectiveness Therapy for Children (SET-C) for children and adolescents with social phobia. The results conclude that both fluoxetine and SET-C are effective for social phobia but SET-C is better for enhancing social skills.
Adult-Onset Fluoxetine Treatment Does Not Improve Behavioral Impairments and May Have Adverse Effects on the Ts65Dn Mouse Model of Down Syndrome

PubMed Central

Heinen, Markus; Hettich, Moritz M.; Ryan, Devon P.; Schnell, Susanne; Paesler, Katharina; Ehninger, Dan

2012-01-01

Down syndrome is caused by triplication of chromosome 21 and is associated with neurocognitive phenotypes ranging from severe intellectual disability to various patterns of more selective neuropsychological deficits, including memory impairments. In the Ts65Dn mouse model of Down syndrome, excessive GABAergic neurotransmission results in local over-inhibition of hippocampal circuits, which dampens hippocampal synaptic plasticity and contributes to cognitive impairments. Treatments with several GABAA receptor antagonists result in increased plasticity and improved memory deficits in Ts65Dn mice. These GABAA receptor antagonists are, however, not suitable for clinical applications. The selective serotonin reuptake inhibitor fluoxetine, in contrast, is a widely prescribed antidepressant that can also enhance plasticity in the adult rodent brain by lowering GABAergic inhibition. For these reasons, we wondered if an adult-onset 4-week oral fluoxetine treatment restores spatial learning and memory impairments in Ts65Dn mice. Fluoxetine did not measurably improve behavioral impairments of Ts65Dn mice. On the contrary, we observed seizures and mortality in fluoxetine-treated Ts65Dn mice, raising the possibility of a drug × genotype interaction with respect to these adverse treatment outcomes. Future studies should re-address this in larger animal cohorts and determine if fluoxetine treatment is associated with adverse treatment effects in individuals with Down syndrome. PMID:22848851
FLUOXETINE PREVENTS 8-OH-DPAT-INDUCED HYPERPHAGIA IN FISCHER INBRED RATS

PubMed Central

Miryala, Chandra Suma Johnson; Maswood, Navin; Uphouse, Lynda

2011-01-01

Ovariectomized, Fischer rats were hormonally primed with 10 μg estradiol benzoate and 50 μg progesterone or were treated with the sesame seed oil vehicle. Food intake was measured 2 hr and 24 hr after treatment with 0.25 mg/kg of the 5-HT1A receptor agonist, (±)-8-hydroxy 2-(di-n-propylamino) tetralin (8-OH-DPAT), 5 mg/kg of the selective serotonin reuptake inhibitor, fluoxetine, or their combination. Consistent with prior studies, two hr food intake of rats given fluoxetine and 8-OH-DPAT did not differ from vehicle controls. 8-OH-DPAT-induced hyperphagia, evident at 2 hr, was blocked by co-treatment with fluoxetine. However, in contrast to prior studies, 5 mg/kg fluoxetine, alone, had only modest effects on food intake. Differences in our experimental protocols and/or the strain of rat may account for the lower anorectic response to fluoxetine. Nevertheless, the absence of a significant response to fluoxetine, alone, coupled with the drug's attenuation of the hyperphagic effect of 8-OH-DPAT, leads to the suggestion that the behavioral response to the combined treatment is more complex than that of simple additivity. Consistent with this suggestion, 24 hr food intake of rats given 8-OH-DPAT and fluoxetine was lower than that of vehicle or 8-OH-DPAT-treated rats. PMID:21281662
Fluoxetine prevents 8-OH-DPAT-induced hyperphagia in Fischer inbred rats.

PubMed

Miryala, Chandra Suma Johnson; Maswood, Navin; Uphouse, Lynda

2011-04-01

Ovariectomized, Fischer rats were hormonally primed with 10 μg estradiol benzoate and 50 μg progesterone or were treated with the sesame seed oil vehicle. Food intake was measured 2 h and 24 h after treatment with 0.25 mg/kg of the 5-HT(1A) receptor agonist, (±)-8-hydroxy 2-(di-n-propylamino) tetralin (8-OH-DPAT), 5 mg/kg of the selective serotonin reuptake inhibitor, fluoxetine, or their combination. Consistent with prior studies, two hour food intake of rats given fluoxetine and 8-OH-DPAT did not differ from vehicle controls. 8-OH-DPAT-induced hyperphagia, evident at 2 h, was blocked by co-treatment with fluoxetine. However, in contrast to prior studies, 5 mg/kg fluoxetine, alone, had only modest effects on food intake. Differences in our experimental protocols and/or the strain of rat may account for the lower anorectic response to fluoxetine. Nevertheless, the absence of a significant response to fluoxetine, alone, coupled with the drug's attenuation of the hyperphagic effect of 8-OH-DPAT, leads to the suggestion that the behavioral response to the combined treatment is more complex than that of simple additivity. Consistent with this suggestion, 24 h food intake of rats given 8-OH-DPAT and fluoxetine was lower than that of vehicle or 8-OH-DPAT-treated rats. Copyright © 2011 Elsevier Inc. All rights reserved.
Antidepressant-like effects of the acute and chronic administration of nicotine in the rat forced swimming test and its interaction with fluoxetine [correction of flouxetine].

PubMed

Vázquez-Palacios, G; Bonilla-Jaime, H; Velázquez-Moctezuma, J

2004-05-01

An antidepressant action of nicotine (NIC) has recently been suggested. Flouxetine, a selective serotonin reuptake inhibitor, is currently the most widely used antidepressant. In the present study, we analyzed the effects of the administration of NIC, fluoxetine (FLX), and the combination of both drugs given acutely, subchronically, and chronically as well as 7 days after chronic administration of these drugs on the forced swim test. Results showed that NIC induced a significant reduction of the time in immobility during the forced swim test (antidepressant effect), with a concomitant increase in swimming activity (serotonergic activation), after acute administration. These effects remain the same after subchronic and chronic administration. FLX failed to induce any effect after acute administration but did induce a significant decrease of immobility and an increase of swimming after subchronic administration. The effect of the chronic administration was significantly larger compared to subchronic administration. The combination of both drugs induced a larger effect than that observed after a single administration but only after subchronic treatment. No effect was observed after the end of the 7-day treatments. Data suggest that NIC has an antidepressant action that is expressed faster than FLX but remains the same later. Thus, cholinergic-serotonergic interactions could play an important role in the treatment of depression.
Fluoxetine and the mitochondria: A review of the toxicological aspects.

PubMed

de Oliveira, Marcos Roberto

2016-09-06

Fluoxetine (a selective serotonin reuptake inhibitor (SSRI)) is used as an antidepressant by modulating the levels of serotonin in the synaptic cleft. Nevertheless, fluoxetine also induces undesirable effects, such as anxiety, sexual dysfunction, sleep disturbances, and gastrointestinal impairments. Fluoxetine has been viewed as an agent that may interfere with cell fate by triggering apoptosis. On the other hand, fluoxetine intake has been associated with increased cancer risk. Nonetheless, data remain contradictory and no conclusions were taken. Several studies demonstrated that fluoxetine interacts with mitochondria triggering apoptosis and/or altering mitochondrial function by modulating the activity of respiratory chain components and enzymes of the Krebs cycle. Furthermore, fluoxetine affects mitochondria-related redox parameters in different experimental models. In this review, data demonstrating the effects of fluoxetine upon mammalian mitochondria are described and discussed, as well as several unsolved questions in this field of research are addressed. A separate section deals with future needs regarding the research involving the impact of fluoxetine treatment upon mitochondria and mitochondria-related signaling. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.
Effect of co-treatment with fluoxetine or mirtazapine and risperidone on the active behaviors and plasma corticosterone concentration in rats subjected to the forced swim test.

PubMed

Rogóż, Zofia; Kabziński, Marcin; Sadaj, Witold; Rachwalska, Paulina; Gądek-Michalska, Anna

2012-01-01

Several clinical reports have postulated a beneficial effect of the addition of a low dose of risperidone to the ongoing treatment with antidepressants in treatment-resistant depression. The present study aimed to examine the effect of treatment with fluoxetine or mirtazapine, given separately or jointly with risperidone, on active behavior and plasma corticosterone level in male Wistar rats subjected to the forced swim test (FST). The obtained results showed that fluoxetine (5 mg/kg), mirtazapine (5 and 10 mg/kg) or risperidone (0.05 and 0.1 mg/kg) did not change the active behavior of rats in the FST. However, co-treatment with fluoxetine (10 mg/kg) and risperidone (0.1 mg/kg) induced an antidepressant-like effect in that test because it significantly increased the swimming time and decreased the immobility time, while combined treatment with mirtazapine at 5 and 10 mg/kg and risperidone at 0.05 and 0.1 mg/kg evoked a significant increase in the swimming time and also climbing, and decreased the immobility time. WAY 100635 (a 5-HT(1A) receptor antagonist) at a dose of 0.1 mg/kg inhibited the antidepressant-like effect induced by co-administration of fluoxetine or mirtazapine and risperidone. Active behavior in that test did not reflect an increase in general activity, since combined treatment with fluoxetine or mirtazapine and risperidone failed to enhance the exploratory activity of rats. Co-treatment with fluoxetine or mirtazapine and risperidone did not reduce the stress-induced increase in plasma corticosterone concentration in animals subjected to the FST. The obtained results indicate that risperidone applied in a low dose enhances the antidepressant-like activity of fluoxetine and mirtazapine in the FST (but does not normalize the stress-induced increase in corticosterone level in these rats), and that 5-HT(1A) receptors may play some role in these effects.
Dual effects of fluoxetine on mouse early embryonic development

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kim, Chang-Woon; Department of Obstetrics and Gynecology, Samsung Changwon Hospital, Sungkyunkwan University, Changwon 630-723; Choe, Changyong

2012-11-15

Fluoxetine, a selective serotonin reuptake inhibitor, regulates a variety of physiological processes, such as cell proliferation and apoptosis, in mammalian cells. Little is known about the role of fluoxetine in early embryonic development. This study was undertaken to investigate the effect of fluoxetine during mouse early embryonic development. Late two-cell stage embryos (2-cells) were cultured in the presence of various concentrations of fluoxetine (1 to 50 μM) for different durations. When late 2-cells were incubated with 5 μM fluoxetine for 6 h, the percentage that developed into blastocysts increased compared to the control value. However, late 2-cells exposed to fluoxetinemore » (5 μM) over 24 h showed a reduction in blastocyst formation. The addition of fluoxetine (5 μM) together with KN93 or KN62 (calcium/calmodulin-dependent protein kinase II (CaMKII) inhibitors) failed to increase blastocyst formation. Fluoxetine treatment inhibited TREK-1 and TREK-2, members of the two-pore domain K{sup +} channel family expressed in mouse embryos, activities, indicating that fluoxetine-induced membrane depolarization in late 2-cells might have resulted from TREK inhibition. In addition, long-term exposure to fluoxetine altered the TREK mRNA expression levels. Furthermore, injection of siRNA targeting TREKs significantly decreased blastocyst formation by ∼ 30% compared to injection of scrambled siRNA. Long-term exposure of fluoxetine had no effect on blastocyst formation of TREK deficient embryos. These results indicate that low-dose and short-term exposures of late 2-cells to fluoxetine probably increase blastocyst formation through activation of CaMKII-dependent signal transduction pathways, whereas long-term exposure decreases mouse early embryonic development through inhibition of TREK channel gating. Highlights: ► Short-term exposure of 2-cells to fluoxetine enhances mouse blastocyst formation. ► The enhancive effect of fluoxetine is resulted from Ca
Morphological and functional determinants of fluoxetine (Prozac)-induced pulmonary disease in an experimental model.

PubMed

Capelozzi, Marco A; Leick-Maldonado, Edna A; Parra, Edwin R; Martins, Mílton A; Tibério, Iolanda F L C; Capelozzi, Vera L

2007-05-14

Fluoxetine treatment effects were determined by evaluating respiratory mechanics (elastance/resistance) and exhaled nitric oxide, as well as mononuclear and polymorphonuclear cell recruitment into the lungs, in an experimental guinea pig model. Guinea pigs were divided into four groups: Fl (fluoxetine only, n=7); Fl+Sw (fluoxetine and forced swimming, n=7); Ns+Sw (normal saline and forced swimming, n=8); and Ns (normal saline only, n=8). Treated animals received oral fluoxetine (10 mg/(kg day)) for 30 consecutive days. On day 31, all animals were anesthetized and mechanically ventilated so that respiratory system elastance and resistance, as well exhaled nitric oxide, could be determined. The lungs were then excised en bloc for histological and immunohistochemical evaluation. Forced swimming induced bronchodilation in untreated animals and bronchoconstriction in fluoxetine-treated animals. Fluoxetine treatment was also associated with mononuclear infiltration (predominantly into alveolar walls) and neutrophil recruitment. In addition, levels of exhaled nitric oxide, an inflammatory marker, were higher in fluoxetine-treated animals. Swimming-induced stress also amplified mononuclear cell recruitment to the lungs. These results show that, in this experimental model, fluoxetine treatment reproduces the pathology of chronic interstitial pneumonia in humans.
12-Month Follow-Up of Fluoxetine and Cognitive Behavioral Therapy for Binge Eating Disorder

ERIC Educational Resources Information Center

Grilo, Carlos M.; Crosby, Ross D.; Wilson, G. Terence; Masheb, Robin M.

2012-01-01

Objective: The longer term efficacy of medication treatments for binge-eating disorder (BED) remains unknown. This study examined the longer term effects of fluoxetine and cognitive behavioral therapy (CBT) either with fluoxetine (CBT + fluoxetine) or with placebo (CBT + placebo) for BED through 12-month follow-up after completing treatments.…
Efficacy and safety of olanzapine/fluoxetine combination in the treatment of treatment-resistant depression: a meta-analysis of randomized controlled trials

PubMed Central

Luan, Shuxin; Wan, Hongquan; Wang, Shijun; Li, He; Zhang, Baogang

2017-01-01

Background Whether olanzapine/fluoxetine combination (OFC) is superior to olanzapine or fluoxetine monotherapy in patients with treatment-resistant depression (TRD) remains controversial. Thus, we conducted this meta-analysis of randomized controlled trials (RCTs) to compare the efficacy and safety of OFC with olanzapine or fluoxetine monotherapy for patients with TRD. Materials and methods RCTs published in PubMed, Embase, Web of Science, and the ClinicalTrials.gov registry were systematically reviewed to assess the efficacy and safety of OFC. Outcomes included mean changes from baseline in Montgomery–Asberg Depression Rating Scale (MADRS), Clinical Global Impression-Severity (CGI-S), Hamilton Rating Scale for Anxiety (HAM-A), Brief Psychiatric Rating Scale (BPRS) scores, response rate, remission rate, and adverse events. Results were expressed with weighted mean difference (WMD) with 95% confidence intervals (CIs) and risk ratio (RR) with 95% CIs. Results A total of five RCTs with 3,020 patients met the inclusion criteria and were included in this meta-analysis. Compared with olanzapine or fluoxetine monotherapy, OFC was associated with greater changes from baseline in MADRS (WMD =−3.37, 95% CI: −4.76, −1.99; P<0.001), HAM-A (WMD =−1.82, 95% CI: −2.25, −1.40; P<0.001), CGI-S (WMD =−0.37, 95% CI: −0.45, −0.28; P<0.001), and BPRS scores (WMD =−1.46, 95% CI: −2.16, −0.76; P<0.001). Moreover, OFC had significantly higher response rate (RR =1.35, 95% CI: 1.12, 1.63; P=0.001) and remission rate (RR =1.71, 95% CI: 1.31, 2.23; P<0.001). The incidence of treatment-related adverse events was similar between the OFC and monotherapy groups (RR =1.01, 95% CI: 0.94, 1.08; P=0.834). Conclusion OFC is more effective than olanzapine or fluoxetine monotherapy in the treatment of patients with TRD. Our results provided supporting evidence for the use of OFC in TRD. However, considering the limitations in this study, more large-scale, well-designed RCTs are
Differential behavioral effects of the antidepressants reboxetine, fluoxetine, and moclobemide in a modified forced swim test following chronic treatment.

PubMed

Cryan, John F; Page, Michelle E; Lucki, Irwin

2005-11-01

The forced swim test (FST) is the most widely used model for assessing potential antidepressant activity in rodents following acute or short-term treatment. However, few studies have compared the effects of short- and long-term antidepressant treatment on behaviors in the test, despite the need to treat patients chronically to produce clinical effects. The current studies examined whether antidepressants from different classes produce different behavioral effects following short-term treatment and whether such effects change following administration for a longer duration. The effects of administering short-term (3 days) and long-term (14 days) treatments of antidepressants from three different chemical classes with distinct mechanisms of action via osmotic minipump were examined: the selective norepinephrine reuptake inhibitor reboxetine (10 and 60 mg kg(-1) day(-1)), the selective serotonin reuptake inhibitor fluoxetine (2.5 and 15 mg kg(-1) day(-1)), and the reversible inhibitor of monoamine oxidase moclobemide (2.5 and 15 mg kg(-1) day(-1)). All testing was carried out in a 15-min test with no preswim session in order to negate any confounding aspect of an induction procedure. The majority of antidepressant-sensitive behavioral changes were observed in the first 5 min of the test. The low dose of reboxetine failed to alter behavior in the test after 3 days but significantly decreased immobility and increased climbing behavior following administration for 14 days, whereas the high dose of reboxetine was equally effective following 3 and 14 days of treatment. In a similar fashion, the low dose of fluoxetine failed to alter behavior in the test following 3 days, but showed an augmented response on immobility and increased swimming following administration for 14 days. The high dose of fluoxetine was slightly more effective at reducing immobility following administration for 14 days than 3 days. The low dose of moclobemide decreased immobility and increased climbing
Males and Females Respond Differently to Controllability and Antidepressant Treatment

PubMed Central

Leuner, Benedetta; Mendolia-Loffredo, Sabrina; Shors, Tracey J.

2012-01-01

Background Women are much more likely to suffer from stress-related mental illness than men; yet few, if any, animal models for such sex differences exist. Previously, we reported that exposure to an acute stressor enhances learning in male rats yet severely impairs learning in female rats. Here, we tested whether these opposite effects in males versus females could be prevented by establishing control over the stressor or by antidepressant treatment. Methods Learning was assessed using the hippocampal-dependent task of trace eyeblink conditioning. In the first experiment, groups of male and female rats were exposed to controllable or uncontrollable stress and trained. In a second experiment, they were exposed to an uncontrollable stressor after chronic treatment with the antidepressant fluoxetine (Prozac). In a final experiment, females were exposed to uncontrollable stress after acute treatment with fluoxetine. Results Establishing control over the stressful experience eliminated the detrimental effect of stress on learning in females as well as the enhancing effect of stress in males. Moreover, chronic but not acute treatment with fluoxetine prevented the learning deficit in females after exposure to stress. Treatment with fluoxetine did not alter the male response to stress. Conclusions These data indicate that males and females not only respond in opposite directions to the same stressful event but also respond differently to controllability and antidepressant treatments. PMID:15601607
Delirium Associated With Fluoxetine Discontinuation: A Case Report.

PubMed

Fan, Kuang-Yuan; Liu, Hsing-Cheng

Withdrawal symptoms on selective serotonin reuptake inhibitor (SSRI) discontinuation have raised clinical attention increasingly. However, delirium is rarely reported in the SSRI discontinuation syndrome. We report a case of delirium developing after fluoxetine discontinuation in a 65-year-old female patient with major depressive disorder. She experienced psychotic depression with limited response to treatment of fluoxetine 40 mg/d and quetiapine 100 mg/d for 3 months. After admission, we tapered fluoxetine gradually in 5 days because of its limited effect. However, delirious pictures developed 2 days after we stopped fluoxetine. Three days later, we added back fluoxetine 10 mg/d. Her delirious features gradually improved, and the clinical presentation turned into previous psychotic depression state. We gradually increased the medication to fluoxetine 60 mg/d and olanzapine 20 mg/d in the following 3 weeks. Her psychotic symptoms decreased, and there has been no delirious picture noted thereafter. Delirium associated with fluoxetine discontinuation is a much rarer complication in SSRI discontinuation syndrome. The symptoms of SSRI discontinuation syndrome may be attributable to a rapid decrease in serotonin availability. In general, the shorter the half-life of any medication, the greater the likelihood patients will experience discontinuation symptoms. Genetic vulnerability might be a potential factor to explain that SSRI discontinuation syndrome also occurred rapidly in people taking long-half-life fluoxetine. The genetic polymorphisms of both pharmacokinetic and pharmacodynamic pathways might be potentially associated with SSRI discontinuation syndrome.
Subchronic treatment with fluoxetine and ketanserin increases hippocampal brain-derived neurotrophic factor, β-catenin and antidepressant-like effects.

PubMed

Pilar-Cuéllar, F; Vidal, R; Pazos, A

2012-02-01

5-HT(2A) receptor antagonists improve antidepressant responses when added to 5-HT-selective reuptake inhibitors (SSRIs) or tricyclic antidepressants. Here, we have studied the involvement of neuroplasticity pathways and/or the 5-hydroxytryptaminergic system in the antidepressant-like effect of this combined treatment, given subchronically. Expression of brain-derived neurotrophic factor (BDNF) and its receptor (TrkB), 5-bromo-2'-deoxyuridine (BrdU) incorporation, and β-catenin protein expression in different cellular fractions, as well as 5-HT(1A) receptor function were measured in the hippocampus of rats treated with fluoxetine, ketanserin and fluoxetine + ketanserin for 7 days, followed by a forced swimming test (FST) to analyse antidepressant efficacy. mRNA for BDNF was increased in the CA3 field and dentate gyrus of the hippocampus by combined treatment with fluoxetine + ketanserin. Expression of β-catenin was increased in total hippocampal homogenate and in the membrane fraction, but unchanged in the nuclear fraction after combined treatment with fluoxetine + ketanserin. These effects were paralleled by a decreased immobility time in the FST. There were no changes in BrdU incorporation, TrkB expression and 5-HT(1A) receptor function in any of the groups studied. The antidepressant-like effect induced by subchronic co-treatment with a SSRI and a 5-HT(2A) receptor antagonist may mainly be because of modifications in hippocampal neuroplasticity (BDNF and membrane-associated β-catenin), without a significant role for other mechanisms involved in chronic antidepressant response, such as hippocampal neuroproliferation or 5-HT(1A) receptor desensitization in the dorsal raphe nucleus. © 2011 The Authors. British Journal of Pharmacology © 2011 The British Pharmacological Society.
Dual effects of fluoxetine on mouse early embryonic development.

PubMed

Kim, Chang-Woon; Choe, Changyong; Kim, Eun-Jin; Lee, Jae-Ik; Yoon, Sook-Young; Cho, Young-Woo; Han, Sunkyu; Tak, Hyun-Min; Han, Jaehee; Kang, Dawon

2012-11-15

Fluoxetine, a selective serotonin reuptake inhibitor, regulates a variety of physiological processes, such as cell proliferation and apoptosis, in mammalian cells. Little is known about the role of fluoxetine in early embryonic development. This study was undertaken to investigate the effect of fluoxetine during mouse early embryonic development. Late two-cell stage embryos (2-cells) were cultured in the presence of various concentrations of fluoxetine (1 to 50μM) for different durations. When late 2-cells were incubated with 5μM fluoxetine for 6h, the percentage that developed into blastocysts increased compared to the control value. However, late 2-cells exposed to fluoxetine (5μM) over 24h showed a reduction in blastocyst formation. The addition of fluoxetine (5μM) together with KN93 or KN62 (calcium/calmodulin-dependent protein kinase II (CaMKII) inhibitors) failed to increase blastocyst formation. Fluoxetine treatment inhibited TREK-1 and TREK-2, members of the two-pore domain K(+) channel family expressed in mouse embryos, activities, indicating that fluoxetine-induced membrane depolarization in late 2-cells might have resulted from TREK inhibition. In addition, long-term exposure to fluoxetine altered the TREK mRNA expression levels. Furthermore, injection of siRNA targeting TREKs significantly decreased blastocyst formation by ~30% compared to injection of scrambled siRNA. Long-term exposure of fluoxetine had no effect on blastocyst formation of TREK deficient embryos. These results indicate that low-dose and short-term exposures of late 2-cells to fluoxetine probably increase blastocyst formation through activation of CaMKII-dependent signal transduction pathways, whereas long-term exposure decreases mouse early embryonic development through inhibition of TREK channel gating. Copyright © 2012 Elsevier Inc. All rights reserved.
Maternal depressive symptoms in pediatric major depressive disorder: relationship to acute treatment outcome.

PubMed

Kennard, Betsy D; Hughes, Jennifer L; Stewart, Sunita M; Mayes, Taryn; Nightingale-Teresi, Jeanne; Tao, Rongrong; Carmody, Thomas; Emslie, Graham J

2008-06-01

In the present study, we assess maternal depressive symptoms at the beginning and end of treatment to investigate the possible reciprocal relationship of maternal illness with the child's depressive illness and treatment. We present data on 146 children and their mothers who were participating in a pediatric acute treatment study of fluoxetine. Patients were assessed with the Children's Depression Rating Scale-Revised at baseline and at each treatment visit. Mothers completed the Quick Inventory of Depressive Symptomatology-Self Report at baseline and end of acute treatment. Thirty percent of mothers had moderate to severe levels of depressive symptoms at the child's baseline assessment. Overall, mothers reported improvement in maternal depressive symptoms at the end of their child's acute treatment, although maternal depression was not specifically targeted for intervention. Furthermore, mother's depressive symptoms appear to be associated with the child's depression severity both at the beginning and end of treatment. Mothers with higher levels of depressive symptoms had children with higher levels of depression severity at baseline and over the course of treatment. However, maternal depressive symptoms at baseline had no association with the rate of improvement of child depression severity. This study indicates a positive relationship between the depression severity of mothers and their children. These findings highlight potential areas of intervention in the acute treatment of childhood depression.
Dysfunctional Attitudes Scale Perfectionism: A Predictor and Partial Mediator of Acute Treatment Outcome among Clinically Depressed Adolescents

PubMed Central

Jacobs, Rachel H.; Silva, Susan G.; Reinecke, Mark A.; Curry, John F.; Ginsburg, Golda S.; Kratochvil, Christopher J.; March, John S.

2009-01-01

The effect of perfectionism on acute treatment outcomes was explored in a randomized controlled trial of 439 clinically depressed adolescents (12–17 years of age) enrolled in the Treatment for Adolescents with Depression Study (TADS) who received cognitive behavior therapy (CBT), fluoxetine, a combination of CBT and FLX, or pill placebo. Measures included the Children’s Depression Rating Scale–Revised, the Suicidal Ideation Questionnaire–Grades 7–9, and the perfectionism subscale from the Dysfunctional Attitudes Scale (DAS). Predictor results indicate that adolescents with higher versus lower DAS perfectionism scores at baseline, regardless of treatment, continued to demonstrate elevated depression scores across the acute treatment period. In the case of suicidality, DAS perfectionism impeded improvement. Treatment outcomes were partially mediated by the change in DAS perfectionism across the 12-week period. PMID:20183664

Fluoxetine Dose and Administration Method Differentially Affect Hippocampal Plasticity in Adult Female Rats

PubMed Central

Pawluski, Jodi L.; van Donkelaar, Eva; Abrams, Zipporah; Steinbusch, Harry W. M.; Charlier, Thierry D.

2014-01-01

Selective serotonin reuptake inhibitor medications are one of the most common treatments for mood disorders. In humans, these medications are taken orally, usually once per day. Unfortunately, administration of antidepressant medications in rodent models is often through injection, oral gavage, or minipump implant, all relatively stressful procedures. The aim of the present study was to investigate how administration of the commonly used SSRI, fluoxetine, via a wafer cookie, compares to fluoxetine administration using an osmotic minipump, with regards to serum drug levels and hippocampal plasticity. For this experiment, adult female Sprague-Dawley rats were divided over the two administration methods: (1) cookie and (2) osmotic minipump and three fluoxetine treatment doses: 0, 5, or 10 mg/kg/day. Results show that a fluoxetine dose of 5 mg/kg/day, but not 10 mg/kg/day, results in comparable serum levels of fluoxetine and its active metabolite norfluoxetine between the two administration methods. Furthermore, minipump administration of fluoxetine resulted in higher levels of cell proliferation in the granule cell layer (GCL) at a 5 mg dose compared to a 10 mg dose. Synaptophysin expression in the GCL, but not CA3, was significantly lower after fluoxetine treatment, regardless of administration method. These data suggest that the administration method and dose of fluoxetine can differentially affect hippocampal plasticity in the adult female rat. PMID:24757568
Fluoxetine Exerts Age-Dependent Effects on Behavior and Amygdala Neuroplasticity in the Rat

PubMed Central

Homberg, Judith R.; Olivier, Jocelien D. A.; Blom, Tom; Arentsen, Tim; van Brunschot, Chantal; Schipper, Pieter; Korte-Bouws, Gerdien; van Luijtelaar, Gilles; Reneman, Liesbeth

2011-01-01

The selective serotonin reuptake inhibitor (SSRI) Prozac® (fluoxetine) is the only registered antidepressant to treat depression in children and adolescents. Yet, while the safety of SSRIs has been well established in adults, serotonin exerts neurotrophic actions in the developing brain and thereby may have harmful effects in adolescents. Here we treated adolescent and adult rats chronically with fluoxetine (12 mg/kg) at postnatal day (PND) 25 to 46 and from PND 67 to 88, respectively, and tested the animals 7–14 days after the last injection when (nor)fluoxetine in blood plasma had been washed out, as determined by HPLC. Plasma (nor)fluoxetine levels were also measured 5 hrs after the last fluoxetine injection, and matched clinical levels. Adolescent rats displayed increased behavioral despair in the forced swim test, which was not seen in adult fluoxetine treated rats. In addition, beneficial effects of fluoxetine on wakefulness as measured by electroencephalography in adults was not seen in adolescent rats, and age-dependent effects on the acoustic startle response and prepulse inhibition were observed. On the other hand, adolescent rats showed resilience to the anorexic effects of fluoxetine. Exploratory behavior in the open field test was not affected by fluoxetine treatment, but anxiety levels in the elevated plus maze test were increased in both adolescent and adult fluoxetine treated rats. Finally, in the amygdala, but not the dorsal raphe nucleus and medial prefrontal cortex, the number of PSA-NCAM (marker for synaptic remodeling) immunoreactive neurons was increased in adolescent rats, and decreased in adult rats, as a consequence of chronic fluoxetine treatment. No fluoxetine-induced changes in 5-HT1A receptor immunoreactivity were observed. In conclusion, we show that fluoxetine exerts both harmful and beneficial age-dependent effects on depressive behavior, body weight and wakefulness, which may relate, in part, to differential fluoxetine
A comparative study of fluoxetine, moclobemide, and tianeptine in the treatment of posttraumatic stress disorder following an earthquake.

PubMed

Onder, E; Tural, U; Aker, T

2006-04-01

Although antidepressant drugs have been proven as an effective treatment for posttraumatic stress disorder (PTSD), there are few comparative studies of antidepressants that are acting on different neurotransmitters. The main aim of this study is to compare the efficacy of different class of antidepressant drugs on the PTSD. SUBJECTS/MATERIALS AND METHODS: In this open label study, the patients who met DSM-IV criteria for PTSD were randomly assigned to flexible doses of fluoxetine, moclobemide, or tianeptine. After the first assessment, consecutive assessments were performed at the end of weeks 2, 4, 8, and 12 using clinician administered PTSD scale (CAPS) and Clinical Global Impression of Severity (CGI-S). Changes in the total score of CAPS and sub-scale scores of symptom clusters (re-experience, avoidance, and hyperarousal) were the main output of efficacy. All statistics were based on intention-to-treat and last-observation-carried-forward (LOCF) principles. Thirty-eight patients were assigned to fluoxetine, 35 patients were assigned to moclobemide, and 30 patients were assigned to tianeptine group. Gender distributions and mean ages of the treatment groups were not significantly different. Drop-out rates due to an adverse events or unknown reasons were not significantly different among fluoxetine (18.4%), moclobemide (14.3%), and tianeptine (20.0%) groups. All three treatments has led to a significant improvement in PTSD severity assessed with CAPS total score (ANOVA P < 0.001). Similarly, total scores of re-experiencing, avoidance, and hyperarousal clusters that are subscales of CAPS were significantly reduced by all three treatments (with ANOVA all P values < 0.001). There was not significant difference in terms of treatment effect between three groups. Treatment groups showed very similar improvement on all ratings scales. The findings support that fluoxetine, moclobemide, and tianeptine are all effective in the treatment of PTSD. Different mechanisms of
Beneficial effects of fluoxetine, reboxetine, venlafaxine, and voluntary running exercise in stressed male rats with anxiety- and depression-like behaviors.

PubMed

Lapmanee, Sarawut; Charoenphandhu, Jantarima; Charoenphandhu, Narattaphol

2013-08-01

Rodents exposed to mild but repetitive stress may develop anxiety- and depression-like behaviors. Whether this stress response could be alleviated by pharmacological treatments or exercise interventions, such as wheel running, was unknown. Herein, we determined anxiety- and depression-like behaviors in restraint stressed rats (2h/day, 5 days/week for 4 weeks) subjected to acute diazepam treatment (30min prior to behavioral test), chronic treatment with fluoxetine, reboxetine or venlafaxine (10mg/kg/day for 4 weeks), and/or 4-week voluntary wheel running. In elevated plus-maze (EPM) and forced swimming tests (FST), stressed rats spent less time in the open arms and had less swimming duration than the control rats, respectively, indicating the presence of anxiety- and depression-like behaviors. Stressed rats also developed learned fear as evaluated by elevated T-maze test (ETM). Although wheel running could reduce anxiety-like behaviors in both EPM and ETM, only diazepam was effective in the EPM, while fluoxetine, reboxetine, and venlafaxine were effective in the ETM. Fluoxetine, reboxetine, and wheel running, but not diazepam and venlafaxine, also reduced depression-like behavior in FST. Combined pharmacological treatment and exercise did not further reduce anxiety-like behavior in stressed rats. However, stressed rats treated with wheel running plus reboxetine or venlafaxine showed an increase in climbing duration in FST. In conclusion, regular exercise (voluntary wheel running) and pharmacological treatments, especially fluoxetine and reboxetine, could alleviate anxiety- and depression-like behaviors in stressed male rats. Copyright © 2013 Elsevier B.V. All rights reserved.
Fluoxetine improves functional work capacity in women with premenstrual dysphoric disorder.

PubMed

Steiner, M; Brown, E; Trzepacz, P; Dillon, J; Berger, C; Carter, D; Reid, R; Stewart, D

2003-02-01

Interference with social and occupational functioning is a key criterion for premenstrual dysphoric disorder (PMDD) and distinguishes it from the less severe premenstrual syndrome (PMS). We conducted a post hoc analysis of the results of a previously reported study evaluating the efficacy of fluoxetine in the management of PMDD, to determine the extent to which women with PMDD perceived impairment in their functional work capacity during the luteal phase of their menstrual cycle. The effects of two doses of fluoxetine vs placebo in alleviating PMDD symptoms and restoring normal work capacity during this period were assessed. We measured baseline follicular vs luteal phase presence of 8 patient-rated functional work capacity-related symptoms on the Premenstrual Tension Scale-Self Rated in 320 women who met diagnostic criteria for late luteal phase dysphoric disorder, now known as PMDD. Women were then randomized to double-blind treatment with either fluoxetine 20 mg/d, fluoxetine 60 mg/d, or placebo daily for 6 menstrual cycles. All 8 work capacity-related symptoms were more likely to be present in the baseline luteal phase than in the baseline follicular phase. A statistically significant improvement from baseline to the average treatment score for the work capacity subscale was detected for both fluoxetine groups compared to the placebo group. This beneficial response to fluoxetine was evident by the first cycle of treatment. Our results demonstrate that fluoxetine at a relatively low dose of 20 mg/d quickly reduced symptoms that negatively affect work capacity and was well tolerated.
Role of neuropeptide Y and proopiomelanocortin in fluoxetine-induced anorexia.

PubMed

Myung, Chang-Seon; Kim, Bom-Taeck; Choi, Si Ho; Song, Gyu Yong; Lee, Seok Yong; Jahng, Jeong Won

2005-06-01

Fluoxetine is an anorexic agent known to reduce food intake and weight gain. However, the molecular mechanism by which fluoxetine induces anorexia has not been well-established. We examined mRNA expression levels of neuropeptide Y (NPY) and proopiomelanocortin (POMC) in the brain regions of rats using RT-PCR and in situ hybridization techniques after 2 weeks of administering fluoxetine daily. Fluoxetine persistently suppressed food intake and weight gain during the experimental period. The pair-fed group confirmed that the reduction in body weight in the fluoxetine treated rats resulted primarily from decreased food intake. RT-PCR analyses showed that mRNA expression levels of both NPY and POMC were markedly reduced by fluoxetine treatment in all parts of the brain examined, including the hypothalamus. POMC mRNA in situ signals were significantly decreased, NPY levels tended to increase in the arcuate nucleus (ARC) of fluoxetine treated rats (compared to the vehicle controls). In the pair-fed group, NPY mRNA levels did not change, but the POMC levels decreased (compared with the vehicle controls). These results reveal that the chronic administration of fluoxetine decreases expression levels in both NPY and POMC in the brain, and suggests that fluoxetine-induced anorexia may not be mediated by changes in the ARC expression of either NPY or POMC. It is possible that a fluoxetine raised level of 5-HT play an inhibitory role in the orectic action caused by a reduced expression of ARC POMC (alpha-MSH).
TREATMENT TRIAL AND LONG-TERM FOLLOW-UP EVALUATION AMONG COMORBID YOUTH WITH MAJOR DEPRESSION AND A CANNABIS USE DISORDER.

PubMed

Cornelius, Jack R; Salloum, Ihsan M; Ferrell, Robert; Douaihy, Antoine B; Hayes, Jeanie; Kirisci, Levent; Horner, Michelle; Daley, Dennis C

2012-01-01

This study compared the acute phase (12-week) and the long-term (1 year) efficacy of fluoxetine versus placebo for the treatment of the depressive symptoms and the cannabis use of youth with comorbid major depressive disorder (MDD) and an cannabis use disorder (CUD)(cannabis dependence or cannabis abuse). We hypothesized that fluoxetine would demonstrate efficacy in the acute phase trial and at the 1-year follow-up evaluation. Data is also provided regarding the prevalence of risky sexual behaviors in our study sample. We recently completed the first double-blind placebo-controlled study of fluoxetine in adolescents and young adults with comorbid MDD/CUD. A total of 70 persons participated in the acute phase trial, and 68 of those persons (97%) also participated in the 1-year follow-up evaluation. Results of the acute phase study have already been presented (Cornelius, Bukstein, et al., 2010), but the results of the 1 year follow-up assessment have not been published previously. All participants in both treatment groups also received manual-based cognitive behavioral therapy (CBT) and motivation enhancement therapy (MET) during the 12-week course of the study. The 1-year follow-up evaluation was conducted to assess whether the clinical improvements noted during the acute phase trial persisted long term. During the acute phase trial, subjects in both the fluoxetine group and the placebo group showed significant within-group improvement in depressive symptoms and in cannabis-related symptoms. However, no significant difference was noted between the floxetine group and the placebo group on any treatment outcome variable during the acute phase trial. End of study levels of depressive symptoms were low in both the fluoxetine group and the placebo group. Most of the clinical improvements in depressive symptoms and for cannabis-related symptoms persisted at the 1-year follow-up evaluation. Fluoxetine did not demonstrate greater efficacy than placebo for treating either
Fluoxetine treatment affects the inflammatory response and microglial function according to the quality of the living environment.

PubMed

Alboni, Silvia; Poggini, Silvia; Garofalo, Stefano; Milior, Giampaolo; El Hajj, Hassan; Lecours, Cynthia; Girard, Isabelle; Gagnon, Steven; Boisjoly-Villeneuve, Samuel; Brunello, Nicoletta; Wolfer, David P; Limatola, Cristina; Tremblay, Marie-Ève; Maggi, Laura; Branchi, Igor

2016-11-01

It has been hypothesized that selective serotonin reuptake inhibitors (SSRIs), the most common treatment for major depression, affect mood through changes in immune function. However, the effects of SSRIs on inflammatory response are contradictory since these act either as anti- or pro-inflammatory drugs. Previous experimental and clinical studies showed that the quality of the living environment moderates the outcome of antidepressant treatment. Therefore, we hypothesized that the interplay between SSRIs and the environment may, at least partially, explain the apparent incongruence regarding the effects of SSRI treatment on the inflammatory response. In order to investigate such interplay, we exposed C57BL/6 mice to chronic stress to induce a depression-like phenotype and, subsequently, to fluoxetine treatment or vehicle (21days) while being exposed to either an enriched or a stressful condition. At the end of treatment, we measured the expression levels of several anti- and pro-inflammatory cytokines and inflammatory mediators in the whole hippocampus and in isolated microglia. We also determined microglial density, distribution, and morphology to investigate their surveillance state. Results show that the effects of fluoxetine treatment on inflammation and microglial function, as compared to vehicle, were dependent on the quality of the living environment. In particular, fluoxetine administered in the enriched condition increased the expression of pro-inflammatory markers compared to vehicle, while treatment in a stressful condition produced anti-inflammatory effects. These findings provide new insights regarding the effects of SSRIs on inflammation, which may be crucial to devise pharmacological strategies aimed at enhancing antidepressant efficacy by means of controlling environmental conditions. Copyright © 2016 Elsevier Inc. All rights reserved.
Protective Effects of Caffeic Acid Phenethyl Ester on Fluoxetine-Induced Hepatotoxicity: An Experimental Study.

PubMed

Yılmaz, Ahmet; Elbey, Bilal; Yazgan, Ümit Can; Dönder, Ahmet; Arslan, Necmi; Arslan, Serkan; Alabalık, Ulaş; Aslanhan, Hamza

2016-01-01

Background. The aim of the study was to analyse the effect of caffeic acid phenethyl ester (CAPE) on fluoxetine-induced hepatotoxicity in rats. Materials and Methods. Group I served as control. Group II received CAPE intraperitoneally. Group III received fluoxetine per orally. Group IV received fluoxetine and CAPE. The total antioxidant capacity (TAC), total oxidant status (TOS), oxidative stress index (OSI), and liver enzymes including paraoxonase-1 (PON-1), aspartate transaminase, and alanine transaminase levels were measured. Liver tissues were processed histopathologically for evaluation of liver injury and to validate the serum enzyme levels. Results. An increase in TOS and OSI and a decrease in TAC and PON-1 levels in serum and liver tissues of Group III were observed compared to Groups I and II. After treatment with CAPE, the level of TOS and OSI decreased while TAC and PON-1 increased in serum and liver in Group IV. Histopathological examination of the liver revealed hepatic injury after fluoxetine treatment and reduction of injury with CAPE treatment. Conclusion. Our results suggested that CAPE treatment provided protection against fluoxetine toxicity. Following CAPE treatment with fluoxetine-induced hepatotoxicity, TOS and OSI levels decreased, whereas PON-1 and TAC increased in the serum and liver.
Efficacy of sequential use of fluoxetine for smoking cessation in elevated depressive symptom smokers.

PubMed

Brown, Richard A; Abrantes, Ana M; Strong, David R; Niaura, Raymond; Kahler, Christopher W; Miller, Ivan W; Price, Lawrence H

2014-02-01

Fluoxetine, a selective serotonin reuptake inhibitor, was examined in the treatment of smokers with elevated depressive symptoms. Specifically, this randomized, open-label clinical trial was designed to evaluate the efficacy of three logical, real-world alternatives for providing smoking cessation treatment to smokers with elevated depressive symptoms. In a sample of 216 smokers (mean Center for Epidemiological Studies Depression Scale score = 11.41), participants were randomly assigned to (a) transdermal nicotine patch (TNP), beginning on quit date and continuing for 8 weeks thereafter; (b) standard administration of antidepressant pharmacotherapy with fluoxetine (20mg), beginning 2 weeks before quit date and continuing for 8 weeks following quit date + TNP (ST-FLUOX); or (c) sequential administration of fluoxetine (20mg), beginning 8 weeks before quit date and continuing for 8 weeks following quit date + TNP (SEQ-FLUOX). All participants received 5 sessions of brief behavioral smoking cessation treatment. Findings indicate that SEQ-FLUOX resulted in significantly higher point prevalence abstinence than ST-FLUOX at 6-month follow-up (OR = 2.35; 95% CI = 1.10-5.02, p < .03), a difference that was reduced at the 12-month assessment. Furthermore, sequential fluoxetine treatment, compared with standard fluoxetine treatment, resulted in significantly lower levels of depressive symptoms throughout smoking cessation treatment (p < .025) and significantly lower nicotine withdrawal-related negative affect (p < .004) immediately after quitting. Findings suggest that if one is going to prescribe fluoxetine for smoking cessation in smokers with elevated depressive symptoms, it is best to begin prescribing fluoxetine well before the target quit date.
Mitochondrial energy metabolism of rat hippocampus after treatment with the antidepressants desipramine and fluoxetine.

PubMed

Villa, Roberto Federico; Ferrari, Federica; Bagini, Laura; Gorini, Antonella; Brunello, Nicoletta; Tascedda, Fabio

2017-07-15

Alterations in mitochondrial functions have been hypothesized to participate in the pathogenesis of depression, because brain bioenergetic abnormalities have been detected in depressed patients by neuroimaging in vivo studies. However, this hypothesis is not clearly demonstrated in experimental studies: some suggest that antidepressants are inhibitors of mitochondrial metabolism, while others observe the opposite. In this study, the effects of 21-day treatment with desipramine (15 mg/kg) and fluoxetine (10 mg/kg) were examined on the energy metabolism of rat hippocampus, evaluating the catalytic activity of regulatory enzymes of mitochondrial energy-yielding metabolic pathways. Because of the micro-heterogeneity of brain mitochondria, we have distinguished between (a) non-synaptic mitochondria (FM) of neuronal perikaryon (post-synaptic compartment) and (b) intra-synaptic light (LM) and heavy (HM) mitochondria (pre-synaptic compartment). Desipramine and fluoxetine changed the catalytic activity of specific enzymes in the different types of mitochondria: (a) in FM, both drugs enhanced cytochrome oxidase and glutamate dehydrogenase, (b) in LM, the overall bioenergetics was unaffected and (c) in HM only desipramine increased malate dehydrogenase and decreased the activities of Electron Transport Chain Complexes. These results integrate the pharmacodynamic features of desipramine and fluoxetine at subcellular level, overcoming the previous conflicting data about the effects of antidepressants on brain energy metabolism, mainly referred to whole brain homogenates or to bulk of cerebral mitochondria. With the differentiation in non-synaptic and intra-synaptic mitochondria, this study demonstrates that desipramine and fluoxetine lead to adjustments in the mitochondrial bioenergetics respect to the energy requirements of pre- and post-synaptic compartments. Copyright © 2017 Elsevier Ltd. All rights reserved.
Fluoxetine Prevents Oligodendrocyte Cell Death by Inhibiting Microglia Activation after Spinal Cord Injury

PubMed Central

Lee, Jee Y.; Kang, So R.

2015-01-01

Abstract Oligodendrocyte cell death and axon demyelination after spinal cord injury (SCI) are known to be important secondary injuries contributing to permanent neurological disability. Thus, blocking oligodendrocyte cell death should be considered for therapeutic intervention after SCI. Here, we demonstrated that fluoxetine, an antidepressant drug, alleviates oligodendrocyte cell death by inhibiting microglia activation after SCI. After injury at the T9 level with a Precision Systems and Instrumentation (Lexington, KY) device, fluoxetine (10 mg/kg, intraperitoneal) was administered once a day for the indicated time points. Immunostaining with CD11b (OX-42) antibody and quantification analysis showed that microglia activation was significantly inhibited by fluoxetine at 5 days after injury. Fluoxetine also significantly inhibited activation of p38 mitogen-activated protein kinase (p38-MAPK) and expression of pro-nerve growth factor (pro-NGF), which is known to mediate oligodendrocyte cell death through the p75 neurotrophin receptor after SCI. In addition, fluoxetine attenuated activation of Ras homolog gene family member A and decreased the level of phosphorylated c-Jun and, ultimately, alleviated caspase-3 activation and significantly reduced cell death of oligodendrocytes at 5 days after SCI. Further, the decrease of myelin basic protein, myelin loss, and axon loss in white matter was also significantly blocked by fluoxetine, as compared to vehicle control. These results suggest that fluoxetine inhibits oligodendrocyte cell death by inhibiting microglia activation and p38-MAPK activation, followed by pro-NGF production after SCI, and provide a potential usage of fluoxetine for a therapeutic agent after acute SCI in humans. PMID:25366938
Mesolimbic effects of the antidepressant fluoxetine in Holtzman rats, a genetic strain with increased vulnerability to stress

PubMed Central

Padilla, Eimeira; Shumake, Jason; Barrett, Douglas W.; Sheridan, Eva C.; Gonzalez-Lima, F.

2011-01-01

This is the first metabolic mapping study of the effects of fluoxetine after learned helplessness training. Antidepressants are the most commonly prescribed medications, but the regions underlying treatment effects in affectively disordered brains are poorly understood. We hypothesized the antidepressant action of fluoxetine would produce adaptations in mesolimbic regions after two weeks of treatment. We used Holtzman rats, a genetic strain showing susceptibility to novelty-evoked hyperactivity and stress-evoked helplessness, to map regional brain metabolic effects caused by fluoxetine treatment. Animals underwent learned helplessness, and subsequently immobility time was scored in the forced swim test (FST). On the next day, animals began receiving two weeks of fluoxetine (5 mg/kg/day) or vehicle and were retested in the FST at the end of drug treatment. Antidepressant behavioral effects of fluoxetine were analyzed using a ratio of immobility during pre- and post-treatment FST sessions. Brains were analyzed for regional metabolic activity using quantitative cytochrome oxidase histochemistry as in our previous study using congenitally helpless rats. Fluoxetine exerted a protective effect against FST-induced immobility behavior in Holtzman rats. Fluoxetine also caused a significant reduction in the mean regional metabolism of the nucleus accumbens shell and the ventral hippocampus as compared to vehicle-treated subjects. Additional networks affected by fluoxetine treatment included the prefrontal-cingulate cortex and brainstem nuclei linked to depression (e.g. habenula, dorsal raphe and interpeduncular nucleus). We concluded that corticolimbic regions such as the prefrontal-cingulate cortex, nucleus accumbens, ventral hippocampus and key brainstem nuclei represent important contributors to the neural network mediating fluoxetine antidepressant action. PMID:21376019
Fluoxetine for the Treatment of Childhood Anxiety Disorders: Open-Label, Long-Term Extension to a Controlled Trial

ERIC Educational Resources Information Center

Clark, Duncan B.; Birmaher, Boris; Axelson, David; Monk, Kelly; Kalas, Catherine; Ehmann, Mary; Bridge, Jeffrey; Wood, D. Scott; Muthen, Bengt; Brent, David

2005-01-01

Objective: To assess the efficacy of fluoxetine for the long-term treatment of children and adolescents with anxiety disorders, including generalized anxiety disorder, separation anxiety disorder, and/or social phobia. Method: Children and adolescents (7-17 years old) with anxiety disorders were studied in open treatment for 1 year after they…
Cell type-specific in vivo expression of genes encoding signalling molecules in the brain in response to chronic mild stress and chronic treatment with fluoxetine.

PubMed

Dong, Lu; Li, Baoman; Verkhratsky, Alexei; Peng, Liang

2015-08-01

Previously, we reported that chronic treatment with fluoxetine increased gene expression of 5-hydroxytryptamine receptor 2B (5-HT2BR), cytosolic phospholipase 2α (cPLA2α), glutamate receptor, ionotropic kainate 2 (GluK2) and adenosine deaminase acting on RNA 2 (ADAR2), in cultured astrocytes and astrocytes freshly isolated from transgenic mice tagged with an astrocyte-specific marker. In contrast, neurones isolated from transgenic mice tagged with a neurone-specific marker and exposed to fluoxetine showed an increase in gene expression of glutamate receptor, ionotropic kainate 4 (GluK4) and 5-hydroxytryptamine receptor 2C (5-HT2CR). In a mouse model of anhedonia, the downregulation of 5-HT2BR, cPLA2α, ADAR2 and GluK4 but not GluK2 and 5-HT2CR was detected. To investigate the effects of chronic mild stress (CMS) and/or fluoxetine treatment on gene expression of 5-HT2BR, 5-HT2CR, cPLA2α, ADAR2, GluK2 and GluK4 specifically in astrocytes and neurones. Transgenic mice tagged with either astrocyte- or neurone-specific markers were exposed to the CMS. Real-time PCR was applied to determine expression of messenger RNA (mRNA). We found that (i) mRNAs of the 5-HT2BR and cPLA2α in astrocytes and GluK4 in neurones were significantly reduced in mice that became anhedonic; the mRNA levels were restored by fluoxetine treatment; (ii) ADAR2 in astrocytes was decreased by the CMS but showed no response to fluoxetine in anhedonic animals; (iii) neither GluK2 expression in astrocytes nor 5-HT2CR expression in neurones were affected in anhedonic animals, although expression of 5-HT2CR mRNA was upregulated by fluoxetine. Our results indicate that the effects of chronic treatment with fluoxetine are not only dependent on the cell type studied but also on the development of anhedonia. This suggests that fluoxetine may affect major depression (MD) patients and healthy people in a different manner.
Treatments for acute bipolar depression: meta-analyses of placebo-controlled, monotherapy trials of anticonvulsants, lithium and antipsychotics.

PubMed

Selle, V; Schalkwijk, S; Vázquez, G H; Baldessarini, R J

2014-03-01

Optimal treatments for bipolar depression, and the relative value of specific drugs for that purpose, remain uncertain, including agents other than antidepressants. We searched for reports of placebo-controlled, monotherapy trials of mood-stabilizing anticonvulsants, second-generation antipsychotics, or lithium for acute major depressive episodes in patients diagnosed with type I or II bipolar disorder and applied random-effects meta-analysis to evaluate their efficacy, comparing outcomes based on standardized mean drug-placebo differences (SMD) in improvement, relative response rates (RR), and number-needed-to-treat (NNT). We identified 24 trials of 10 treatments (lasting 7.5 weeks, with ≥ 50 collaborating sites/trial) that met eligibility criteria: lamotrigine (5 trials), quetiapine (5), valproate (4), 2 each for aripiprazole, olanzapine, ziprasidone, and 1 each for carbamazepine, lithium, lurasidone, and olanzapine-fluoxetine. Overall, pooled drug-over-placebo responder-rate superiority (RR) was moderate (29% [CI: 19-40%]), and NNT was 8.2 (CI: 6.4-11). By SMD, apparent efficacy ranked: olanzapine + fluoxetine ≥ valproate > quetiapine > lurasidone > olanzapine, aripiprazole, and carbamazepine; ziprasidone was ineffective, and lithium remains inadequately studied. Notably, drugs were superior to placebo in only 11/24 trials (5/5 with quetiapine, 2/4 with valproate), and only lamotrigine, quetiapine and valproate had > 2 trials. Treatment-associated mania-like reactions were uncommon (drugs: 3.7%; placebo: 4.7%). Controlled trials of non-antidepressant treatments for bipolar depression remain scarce, but findings with olanzapine-fluoxetine, lurasidone, quetiapine, and perhaps carbamazepine and valproate were encouraging; lithium requires adequate testing. © Georg Thieme Verlag KG Stuttgart · New York.
Fatal serotonin toxicity caused by moclobemide and fluoxetine overdose.

PubMed

Wu, Ming-Ling; Deng, Jou-Fang

2011-01-01

Both moclobemide and fluoxetine are used in the treatment of depression, and have been shown to produce fewer side effects than conventional tricyclic antidepressants. A combination of moclobemide and fluoxetine has been used in refractory depression, however there is potential for severe serotonin toxicity. We describe a lethal case of serotonin toxicity in a 36 year-old woman after she ingested multiple drugs, including moclobemide 4500 mg, fluoxetine 200 mg, propranolol 300 mg and several benzodiazepines. The clinical features included coma, mydriasis, hyperthermia, tremor, hyperreflexia, rhabdomyolysis, renal failure and respiratory insufficiency. Eventually, the patient died of disseminated intravascular coagulation and circulatory collapse at 22.5 h postingestion. Toxicological analysis of the patient's blood confirmed high levels of moclobemide 150 μg/mL (therapeutic 1-3 μg/mL), fluoxetine 3750 ng/mL (therapeutic 47-469 ng/mL) and several benzodiazepines. In conclusion, a combination of moclobemide and fluoxetine should be avoided in depressed patients with high suicidal tendencies. Moreover, early recognition and aggressive intervention are the mainstays in the management of potentially life-threatening serotonin toxicity.
Effects of fluoxetine treatment on striatal dopamine transporter binding and cerebrospinal fluid insulin-like growth factor-1 in children with autism.

PubMed

Makkonen, I; Kokki, H; Kuikka, J; Turpeinen, U; Riikonen, R

2011-10-01

A positive effect of fluoxetine has been shown in some children with autism. The present study was undertaken to correlate striatal dopamine transporter (DAT) binding and cerebrospinal fluid insulin-like growth factor-1 (CSF-IGF-1) with clinical response in autistic children (n=13, age 5-16 years) after a 6-month fluoxetine treatment. Good clinical responders (n=6) had a decrease (p=0.031) in DAT binding as assessed using single-photon emission computed tomography with [123I]-nor-β-CIT, whereas poor responders had a trend to an increase. An increase in CSF-IGF-1 (p=0.003) was detected after the treatment period, but no correlation between the clinical response and CSF-IGF-1 was found. In conclusion, fluoxetine decreases DAT binding indicating alleviation of the hyperdopaminergic state and increases CSF-IGF-1 concentration, which may also have a neuroprotective effect against dopamine-induced neurotoxicity in autistic children. © Georg Thieme Verlag KG Stuttgart · New York.
Chronic fluoxetine treatment induces anxiolytic responses and altered social behaviors in medaka, Oryzias latipes.

PubMed

Ansai, Satoshi; Hosokawa, Hiroshi; Maegawa, Shingo; Kinoshita, Masato

2016-04-15

Medaka (Oryzias latipes) is a small freshwater teleost that is an emerging model system for neurobehavioral research and toxicological testing. The selective serotonin reuptake inhibitor class of antidepressants such as fluoxetine is one of the widely prescribed drugs, but little is known about the effects of these drugs on medaka behaviors. To assess the behavioral effects of fluoxetine, we chronically administrated fluoxetine to medaka adult fish and analyzed the anxiety-related and social behaviors using five behavioral paradigms (diving, open-field, light-dark transition, mirror-biting, and social interaction) with an automated behavioral testing system. Fish chronically treated with fluoxetine exhibited anxiolytic responses such as an overall increased time spent in the top area in the diving test and an increased time spent in center area in the open-field test. Analysis of socially evoked behavior showed that chronic fluoxetine administration decreased the number of mirror biting times in the mirror-biting test and increased latency to first contact in the social interaction test. Additionally, chronic fluoxetine administration reduced the horizontal locomotor activity in the open-field test but not the vertical activity in the diving test. These investigations are mostly consistent with previous reports in the other teleost species and rodent models. These results indicate that behavioral assessment in medaka adult fish will become useful for screening of effects of pharmaceutical and toxicological compounds in animal behaviors. Copyright © 2016 Elsevier B.V. All rights reserved.
Serotoninergic manipulation, meal-induced satiety and eating pattern: effect of fluoxetine in obese female subjects.

PubMed

Lawton, C L; Wales, J K; Hill, A J; Blundell, J E

1995-07-01

Twelve nondepressed healthy female obese subjects (BMI > 30 kg/m2) took part in a study which conformed to a double-blind randomized crossover design. Each subject acted as her own control across 2 weeks of treatment with either 60 mg of the 5-HT reuptake inhibitor fluoxetine or matching placebo. On days 7 and 14 of both treatment phases subjects were provided with fixed energy lunch meals high in either CHO or fat. The effect of these meals on satiety during the fluoxetine and placebo phases was assessed by a battery of procedures. Subjects felt less hungry after consuming the high CHO meal than after consuming the high-fat meal. They also felt less hungry when taking fluoxetine than when taking the placebo. Analysis of energy intake from the test meal revealed a main effect of prior lunch meal type (high CHO or high fat) and a main effect of drug treatment. Subjects consumed an average of 574 kcal following the high CHO meal compared to 689 kcal following the high-fat meal. Subjects also consumed an average of 532 kcal when taking fluoxetine compared to 730 kcal when taking the placebo. Fluoxetine did not exert any significant effects on macronutrient selection. Mean daily energy intake, calculated from food diary records, was 1881 kcal when subjects were taking the placebo compared to 1460 kcal when taking fluoxetine (a reduction of 22.4%). Fluoxetine treatment produced a significant weight loss of 1.97 kg over the two weeks of treatment compared to a weight loss of only 0.04 kg on placebo.

Influence of gasoline inhalation on the enantioselective pharmacokinetics of fluoxetine in rats.

PubMed

Cardoso, Juciane Lauren Cavalcanti; Lanchote, Vera Lucia; Pereira, Maria Paula Marques; Capela, Jorge Manuel Vieira; Lepera, José Salvador

2013-03-01

Fluoxetine is used clinically as a racemic mixture of (+)-(S) and (-)-(R) enantiomers for the treatment of depression. CYP2D6 catalyzes the metabolism of both fluoxetine enantiomers. We aimed to evaluate whether exposure to gasoline results in CYP2D inhibition. Male Wistar rats exposed to filtered air (n = 36; control group) or to 600 ppm of gasoline (n = 36) in a nose-only inhalation exposure chamber for 6 weeks (6 h/day, 5 days/week) received a single oral 10-mg/kg dose of racemic fluoxetine. Fluoxetine enantiomers in plasma samples were analyzed by a validated analytical method using LC-MS/MS. The separation of fluoxetine enantiomers was performed in a Chirobiotic V column using as the mobile phase a mixture of ethanol:ammonium acetate 15 mM. Higher plasma concentrations of the (+)-(S)-fluoxetine enantiomer were found in the control group (enantiomeric ratio AUC((+)-(S)/(-)-(R)) = 1.68). In animals exposed to gasoline, we observed an increase in AUC(0-∞) for both enantiomers, with a sharper increase seen for the (-)-(R)-fluoxetine enantiomer (enantiomeric ratio AUC((+)-(S)/(-)-(R)) = 1.07), resulting in a loss of enantioselectivity. Exposure to gasoline was found to result in the loss of enantioselectivity of fluoxetine, with the predominant reduction occurring in the clearance of the (-)-(R)-fluoxetine enantiomer (55% vs. 30%). Copyright © 2013 Wiley Periodicals, Inc.
Fluoxetine: clinical pharmacology and physiologic disposition

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lemberger, L.; Bergstrom, R.F.; Wolen, R.L.

Fluoxetine (30 mg), administered for 7 days to normal volunteers, produced a 66% inhibition of tritiated serotonin uptake into platelets. Plasma concentrations of fluoxetine correlated positively with inhibition of serotonin uptake. Fluoxetine is well absorbed after oral administration in both the fed and fasted states and demonstrates dose proportionality. Fluoxetine disappears from plasma with a half-life of 1-3 days; its metabolite norfluoxetine has a plasma half-life of 7-15 days. After administration of /sup 14/C-fluoxetine, approximately 65% of the administered dose of radioactivity is recovered in urine and about 15% in feces. Fluoxetine, given as a single dose or in multiplemore » doses over 8 days, did not produce significant effects on the plasma disappearance of warfarin, diazepam, tolbutamide, or chlorothiazide. Coadministration of fluoxetine and ethanol did not result in an increase from control values in the blood ethanol levels, nor did it produce significant changes in physiologic, psychometric, or psychomotor activity. Pharmacokinetics of fluoxetine in the elderly and normal volunteers appear to be similar. In addition, pharmacokinetic analyses in patients with varying degrees of renal impairment did not show significant differences from healthy subjects.« less
Effects of nitric oxide synthesis inhibitor or fluoxetine treatment on depression-like state and cardiovascular changes induced by chronic variable stress in rats.

PubMed

Almeida, Jeferson; Duarte, Josiane O; Oliveira, Leandro A; Crestani, Carlos C

2015-01-01

Comorbidity between mood disorders and cardiovascular disease has been described extensively. However, available antidepressants can have cardiovascular side effects. Treatment with selective inhibitors of neuronal nitric oxide synthase (nNOS) induces antidepressant effects, but whether the antidepressant-like effects of these drugs are followed by cardiovascular changes has not been previously investigated. Here, we tested in male rats exposed to chronic variable stress (CVS) the hypothesis that nNOS blockers are advantageous compared with conventional antidepressants in terms of cardiovascular side effects. We compared the effects of chronic treatment with the preferential nNOS inhibitor 7-nitroindazole (7-NI) with those evoked by the conventional antidepressant fluoxetine on alterations that are considered as markers of depression (immobility in the forced swimming test, FST, decreased body weight gain and increased plasma corticosterone concentration) and cardiovascular changes caused by CVS. Rats were exposed to a 14-day CVS protocol, while being concurrently treated daily with either 7-NI (30 mg/kg) or fluoxetine (10 mg/kg). Fluoxetine and 7-NI prevented the increase in immobility in the FST induced by CVS and reduced plasma corticosterone concentration in stressed rats. Both these treatments also prevented the CVS-evoked reduction of the depressor response to vasodilator agents and baroreflex changes. Fluoxetine and 7-NI-induced cardiovascular changes independent of stress exposure, including cardiac autonomic imbalance, increased intrinsic heart rate and vascular sympathetic modulation, a reduction of the pressor response to vasoconstrictor agents, and impairment of baroreflex activity. Altogether, these findings provide evidence that fluoxetine and 7-NI have similar effects on the depression-like state induced by CVS and on cardiovascular function.
Long-term consequences of chronic fluoxetine exposure on the expression of myelination-related genes in the rat hippocampus

PubMed Central

Kroeze, Y; Peeters, D; Boulle, F; van den Hove, D L A; van Bokhoven, H; Zhou, H; Homberg, J R

2015-01-01

The selective serotonin reuptake inhibitor (SSRI) fluoxetine is widely prescribed for the treatment of symptoms related to a variety of psychiatric disorders. After chronic SSRI treatment, some symptoms remediate on the long term, but the underlying mechanisms are not yet well understood. Here we studied the long-term consequences (40 days after treatment) of chronic fluoxetine exposure on genome-wide gene expression. During the treatment period, we measured body weight; and 1 week after treatment, cessation behavior in an SSRI-sensitive anxiety test was assessed. Gene expression was assessed in hippocampal tissue of adult rats using transcriptome analysis and several differentially expressed genes were validated in independent samples. Gene ontology analysis showed that upregulated genes induced by chronic fluoxetine exposure were significantly enriched for genes involved in myelination. We also investigated the expression of myelination-related genes in adult rats exposed to fluoxetine at early life and found two myelination-related genes (Transferrin (Tf) and Ciliary neurotrophic factor (Cntf)) that were downregulated by chronic fluoxetine exposure. Cntf, a neurotrophic factor involved in myelination, showed regulation in opposite direction in the adult versus neonatally fluoxetine-exposed groups. Expression of myelination-related genes correlated negatively with anxiety-like behavior in both adult and neonatally fluoxetine-exposed rats. In conclusion, our data reveal that chronic fluoxetine exposure causes on the long-term changes in expression of genes involved in myelination, a process that shapes brain connectivity and contributes to symptoms of psychiatric disorders. PMID:26393488
Fluoxetine, Smoking, and History of Major Depression: A Randomized Controlled Trial

ERIC Educational Resources Information Center

Spring, Bonnie; Doran, Neal; Pagoto, Sherry; McChargue, Dennis; Cook, Jessica Werth; Bailey, Katherine; Crayton, John; Hedeker, Donald

2007-01-01

The study was a randomized placebo-controlled trial testing whether fluoxetine selectively enhances cessation for smokers with a history of depression. Euthymic smokers with (H+, n = 109) or without (H-, n = 138) a history of major depression received 60 mg fluoxetine or placebo plus group behavioral quit-smoking treatment for 12 weeks. Fluoxetine…
Fluoxetine combined with clorazepate dipotassium and behaviour modification for treatment of anxiety-related disorders in dogs.

PubMed

Pineda, S; Anzola, B; Olivares, A; Ibáñez, M

2014-03-01

The effectiveness of clorazepate dipotassium combined with fluoxetine and a behaviour modification programme for the treatment of anxiety disorders in dogs was investigated. Forty dogs with anxiety disorders were initially enrolled and 36 dogs completed the trial. Dogs were classified into two behavioural categories (anxious dogs with aggression and anxious dogs without aggression) according to their presenting complaints, and were also subdivided into males, females, juveniles and adults. The dog owners were provided with a behaviour modification plan for their dogs to be commenced in the first week of therapy. Clorazepate dipotassium was administered PO at 1.0 mg/kg every 24 h for 4 weeks, and fluoxetine was administered PO at 1.0 mg/kg every 24 h for 10 weeks. Therapy with both drugs was initiated simultaneously. Improvement was reported in 25/36 dogs. Significant differences in treatment effects were observed between anxious dogs with aggression and anxious dogs without aggression (P<0.05). Positive correlations between owner compliance with the treatment plan and reported improvement achieved during three periods of study were also noted. Copyright © 2013 Elsevier Ltd. All rights reserved.
Increasing spinal 5-HT2A receptor responsiveness mediates anti-allodynic effect and potentiates fluoxetine efficacy in neuropathic rats. Evidence for GABA release.

PubMed

Dupuis, Amandine; Wattiez, Anne-Sophie; Pinguet, Jérémy; Richard, Damien; Libert, Frédéric; Chalus, Maryse; Aissouni, Youssef; Sion, Benoit; Ardid, Denis; Marin, Philippe; Eschalier, Alain; Courteix, Christine

2017-04-01

Antidepressants are one of the first line treatments for neuropathic pain but their use is limited by the incidence and severity of side effects of tricyclics and the weak effectiveness of selective serotonin reuptake inhibitors (SSRIs). Serotonin type 2A (5-HT 2A ) receptors interact with PDZ proteins that regulate their functionality and SSRI efficacy to alleviate pain. We investigated whether an interfering peptide (TAT-2ASCV) disrupting the interaction between 5-HT 2A receptors and associated PDZ proteins would improve the treatment of traumatic neuropathic allodynia. Tactile allodynia was assessed in spinal nerve ligation-induced neuropathic pain in rats using von Frey filaments after acute treatment with TAT-2ASCV and/or 5-HT 2A receptor agonist, alone or in combination with repeated treatment with fluoxetine. In vivo microdialysis was performed in order to examine the involvement of GABA in TAT-2ASCV/fluoxetine treatment-associated analgesia. TAT-2ASCV (100ng, single i.t. injection) improved SNL-induced tactile allodynia by increasing 5-HT 2A receptor responsiveness to endogenous 5-HT. Fluoxetine alone (10mg/kg, five i.p. injections) slightly increased tactile thresholds and its co-administration with TAT-2ASCV (100ng, single i.t. injection) further enhanced the anti-allodynic effect. This effect depends on the integrity of descending serotonergic bulbospinal pathways and spinal release of GABA. The anti-allodynic effect of fluoxetine can be enhanced by disrupting 5-HT 2A receptor-PDZ protein interactions. This enhancement depends on 5-HT 2A receptor activation, spinal GABA release and GABAA receptor activation. Copyright © 2016 Elsevier Ltd. All rights reserved.
Treatment of Transvestic Fetishism With Fluoxetine: A Case Report

PubMed Central

Usmani, Mohammad Amir; K Gaur, Rakesh; Ahmad Azmi, Suhail; Gangwar, Sheshank

2012-01-01

Transvestic fetishism is having a sexual or erotic interest in cross-dressing. This case report describes a 17-year-old male with transvestic fetishism who suffered from obsessive thoughts and subsequent masturbation as compulsion. He was managed successfully with fluoxetine. PMID:24644490
Sleep disturbance as detected by actigraphy in pre-pubertal juvenile monkeys receiving therapeutic doses of fluoxetine

PubMed Central

Golub, Mari S.; Hogrefe, Casey E.

2016-01-01

Sleep disturbance is a reported side effect of antidepressant drugs in children. Using a nonhuman primate model of childhood selective serotonin reuptake inhibitor (SSRI) therapy, sleep was studied quantitatively with actigraphy. Two 48-h sessions were recorded in the home cage environment of juvenile male rhesus monkeys at two and three years of age, after one and two years of treatment with a therapeutic dose of the SSRI fluoxetine, and compared to vehicle treated controls. A third session was conducted one year after discontinuation of treatment at four years of age. During treatment, the fluoxetine group demonstrated sleep fragmentation as indexed by a greater number of rest-activity transitions compared to controls. In addition fluoxetine led to more inactivity during the day as indexed by longer duration of rest periods and the reduced activity during these periods. The fluoxetine effect on sleep fragmentation, but not on daytime rest, was modified by the monkey’s genotype for polymorphisms of monoamine oxidase A (MAOA), an enzyme that metabolizes serotonin. After treatment, the fluoxetine effect on nighttime rest-activity transitions persisted, but daytime activity was not affected. The demonstration in this nonhuman primate model of sleep disturbance in connection with fluoxetine treatment and specific genetic polymorphisms, and in the absence of diagnosed psychopathology, can help inform use of this drug in children. PMID:26956991
Sleep disturbance as detected by actigraphy in pre-pubertal juvenile monkeys receiving therapeutic doses of fluoxetine.

PubMed

Golub, Mari S; Hogrefe, Casey E

2016-01-01

Sleep disturbance is a reported side effect of antidepressant drugs in children. Using a nonhuman primate model of childhood selective serotonin reuptake inhibitor (SSRI) therapy, sleep was studied quantitatively with actigraphy. Two 48-h sessions were recorded in the home cage environment of juvenile male rhesus monkeys at two and three years of age, after one and two years of treatment with a therapeutic dose of the SSRI fluoxetine, and compared to vehicle treated controls. A third session was conducted one year after discontinuation of treatment at four years of age. During treatment, the fluoxetine group demonstrated sleep fragmentation as indexed by a greater number of rest-activity transitions compared to controls. In addition fluoxetine led to more inactivity during the day as indexed by longer duration of rest periods and the reduced activity during these periods. The fluoxetine effect on sleep fragmentation, but not on daytime rest, was modified by the monkey's genotype for polymorphisms of monoamine oxidase A (MAOA), an enzyme that metabolizes serotonin. After treatment, the fluoxetine effect on nighttime rest-activity transitions persisted, but daytime activity was not affected. The demonstration in this nonhuman primate model of sleep disturbance in connection with fluoxetine treatment and specific genetic polymorphisms, and in the absence of diagnosed psychopathology, can help inform use of this drug in children. Copyright © 2016 Elsevier Inc. All rights reserved.
Immunomodulatory effects of fluoxetine: A new potential pharmacological action for a classic antidepressant drug?

PubMed

Di Rosso, María Emilia; Palumbo, María Laura; Genaro, Ana María

2016-07-01

Selective serotonin reuptake inhibitors are frequently used antidepressants. In particular, fluoxetine is usually chosen for the treatment of the symptoms of depression, obsessive-compulsive, panic attack and bulimia nervosa. Antidepressant therapy has been associated with immune dysfunction. However, there is contradictory evidence about the effect of fluoxetine on the immune system. Experimental findings indicate that lymphocytes express the serotonin transporter. Moreover it has been shown that fluoxetine is able to modulate the immune function through a serotonin-dependent pathway and through a novel independent mechanism. In addition, several studies have shown that fluoxetine can alter tumor cell viability. Thus, it was recently demonstrated in vivo that chronic fluoxetine treatment inhibits tumor growth by increasing antitumor T-cell activity. Here we briefly review some of the literature referring to how fluoxetine is able to modify, for better or worse, the functionality of the immune system. These results of our analysis point to the relevance of the novel pharmacological action of this drug as an immunomodulator helping to treat several pathologies in which immune deficiency and/or deregulation is present. Copyright © 2015 Elsevier Ltd. All rights reserved.
Remission and Recovery in the Treatment for Adolescents with Depression Study (TADS): Acute and Long-term Outcomes

PubMed Central

Kennard, Betsy D.; Silva, Susan G.; Tonev, Simon; Rohde, Paul; Hughes, Jennifer L.; Vitiello, Benedetto; Kratochvil, Christopher J.; Curry, John F.; Emslie, Graham J.; Reinecke, Mark; March, John

2010-01-01

Objective We examine remission rate probabilities, recovery rates, and residual symptoms across 36 weeks in the Treatment for Adolescents with Depression Study (TADS). Method TADS, a multisite clinical trial, randomized 439 adolescents with major depressive disorder (MDD) to 12 weeks of treatment to fluoxetine (FLX), cognitive behavioral therapy (CBT), their combination (COMB), or pill placebo (PBO). The PBO group, treated openly after week 12, was not included in the subsequent analyses. Treatment differences in remission rates and probabilities of remission over time are compared. Recovery rates in remitters at week 12 (acute phase remitters) and week 18 (continuation phase remitters) are summarized. We also examined whether residual symptoms at the end of 12 weeks of acute treatment predicted later remission. Results At Week 36, the estimated remission rates for intention-to-treat cases were: COMB: 60%, FLX: 55%; CBT: 64%; overall: 60%. Paired comparisons reveal that at week 24 all active treatments converge on remission outcomes. The recovery rate at Week 36 was 65% for acute phase remitters and 71% for continuation phase remitters, with no significant between-treatment differences in recovery rates. Residual symptoms at the end of acute treatment predicted failure to achieve remission at weeks 18 and 36. Conclusions The majority of depressed adolescents in all three treatment modalities achieved remission at the end of nine months of treatment. PMID:19127172
An evaluation of behavioural endpoints: The pharmaceutical pollutant fluoxetine decreases aggression across multiple contexts in round goby (Neogobius melanostomus).

PubMed

McCallum, Erin S; Bose, Aneesh P H; Warriner, Theresa R; Balshine, Sigal

2017-05-01

Fluoxetine (Prozac™) is designed to alter human behaviour; however, because many physiological pathways are conserved across vertebrates, this drug may affect the behaviour of fish living in fluoxetine-polluted environments. Although a number of studies have used behaviour to document the sub-lethal effects of fluoxetine, the repeatability of these effects across experiments, across behavioural contexts, and over different exposure durations are rarely considered. Here, we conducted two experiments and assessed how fluoxetine exposure affected a range of fitness-related behaviours in wild round goby (Neogobius melanostomus). We found that fluoxetine impacts round goby behaviour at high (40 μg/l) doses, but not at environmentally relevant low doses (1 μg/l). In both experiments, an acute 3-day exposure to fluoxetine reduced round goby aggression in multiple behavioural contexts, but had no detectable effect on overall activity or social affiliative behaviour. While a chronic 28-day exposure to fluoxetine exposure still reduced aggression, this reduction was only detectable in one behavioural context. Our findings demonstrate the importance of repeated behavioural testing (both between and within experiments) and contribute to a growing body of literature evaluating the effects of fluoxetine and other pharmaceuticals on animal behaviour. Copyright © 2017 Elsevier Ltd. All rights reserved.
Lack of efficacy for fluoxetine in PTSD: a placebo controlled trial in combat veterans.

PubMed

Hertzberg, M A; Feldman, M E; Beckham, J C; Kudler, H S; Davidson, J R

2000-06-01

Fluoxetine and placebo were studied in a population of combat veterans with severe, chronic PTSD. Twelve male veterans with PTSD were enrolled in a 12 week double-blind evaluation of fluoxetine and placebo. Mean fluoxetine dose at endpoint (week 12) was 48 mg/day with a range of 10 mg to 60 mg. One fluoxetine patient responded (17%) and two of the six placebo patients responded (33%). Fluoxetine patients did not show a greater response than placebo patients in this small sample of male combat veterans with severe, chronic PTSD. Fluoxetine has displayed an efficacious response in controlled studies of patients with PTSD who were predominantly female, suffered civilian (noncombat) traumas, and were overall experiencing less severe PTSD. The reasons for the low response rate to fluoxetine in our study is unknown and will await further study examining variables other than symptoms that might influence outcome, such as gender, comorbidity, prior treatment history, trauma type, severity and chronicity.
Fluoxetine a novel anti-hepatitis C virus agent via ROS-, JNK-, and PPARβ/γ-dependent pathways.

PubMed

Young, Kung-Chia; Bai, Chyi-Huey; Su, Hui-Chen; Tsai, Pei-Ju; Pu, Chien-Yu; Liao, Chao-Sheng; Lin, Yu-Min; Lai, Hsin-Wen; Chong, Lee-Won; Tsai, Yau-Sheng; Tsao, Chiung-Wen

2014-10-01

More than 20% of chronic hepatitis C (CHC) patients receiving interferon-alpha (IFN-α)-based anti-hepatitis C virus (HCV) therapy experienced significant depression, which was relieved by treatment with fluoxetine. However, whether and how fluoxetine affected directly the anti-HCV therapy remained unclear. Here, we demonstrated that fluoxetine inhibited HCV infection and blocked the production of reactive oxygen species (ROS) and lipid accumulation in Huh7.5 cells. Fluoxetine facilitated the IFN-α-mediated antiviral actions via activations of signal transducer and activator of transcription (STAT)-1 and c-Jun amino-terminal kinases (JNK). Alternatively, fluoxetine elevated peroxisome proliferator-activated receptor (PPAR) response element activity under HCV infection. The inhibitory effects of fluoxetine on HCV infection and lipid accumulation, but not production of ROS, were partially reversed by the PPAR-β, -γ, and JNK antagonists. Furthermore, fluoxetine intervention to the IFN-α-2b regimen facilitated to reduce HCV titer and alanine transaminase level for CHC patients. Therefore, fluoxetine intervention to the IFN-α-2b regimen improved the efficacy of anti-HCV treatment, which might be related to blockades of ROS generation and lipid accumulation and activation of host antiviral JNK/STAT-1 and PPARβ/γ signals. Copyright © 2014 Elsevier B.V. All rights reserved.
Fluoxetine for vestibular dysfunction and anxiety: a prospective pilot study.

PubMed

Simon, Naomi M; Parker, Stephen W; Wernick-Robinson, Mara; Oppenheimer, Julia E; Hoge, Elizabeth A; Worthington, John J; Korbly, Nicole B; Pollack, Mark H

2005-01-01

Anxiety states and disorders amplify the symptoms and impairment associated with vestibular dysfunction. Five patients with inner ear vestibular dysfunction and anxiety were prospectively treated with fluoxetine, 20-60 mg/day, and received an extensive battery of assessments at baseline and after 12 weeks of treatment. Fluoxetine led to significant or near significant reductions in anxiety measures and in impairment due to dizziness; improvements in clinical balance function and vestibular function were less clear. The data add to the literature suggesting a role for selective serotonin reuptake inhibitors in the treatment of dizziness and anxiety.
Chronic Fluoxetine Induces the Enlargement of Perforant Path-Granule Cell Synapses in the Mouse Dentate Gyrus

PubMed Central

Kitahara, Yosuke; Ohta, Keisuke; Hasuo, Hiroshi; Shuto, Takahide; Kuroiwa, Mahomi; Sotogaku, Naoki; Togo, Akinobu; Nakamura, Kei-ichiro; Nishi, Akinori

2016-01-01

A selective serotonin reuptake inhibitor is the most commonly prescribed antidepressant for the treatment of major depression. However, the mechanisms underlying the actions of selective serotonin reuptake inhibitors are not fully understood. In the dentate gyrus, chronic fluoxetine treatment induces increased excitability of mature granule cells (GCs) as well as neurogenesis. The major input to the dentate gyrus is the perforant path axons (boutons) from the entorhinal cortex (layer II). Through voltage-sensitive dye imaging, we found that the excitatory neurotransmission of the perforant path synapse onto the GCs in the middle molecular layer of the mouse dentate gyrus (perforant path-GC synapse) is enhanced after chronic fluoxetine treatment (15 mg/kg/day, 14 days). Therefore, we further examined whether chronic fluoxetine treatment affects the morphology of the perforant path-GC synapse, using FIB/SEM (focused ion beam/scanning electron microscopy). A three-dimensional reconstruction of dendritic spines revealed the appearance of extremely large-sized spines after chronic fluoxetine treatment. The large-sized spines had a postsynaptic density with a large volume. However, chronic fluoxetine treatment did not affect spine density. The presynaptic boutons that were in contact with the large-sized spines were large in volume, and the volumes of the mitochondria and synaptic vesicles inside the boutons were correlated with the size of the boutons. Thus, the large-sized perforant path-GC synapse induced by chronic fluoxetine treatment contains synaptic components that correlate with the synapse size and that may be involved in enhanced glutamatergic neurotransmission. PMID:26788851
Differential interaction with the serotonin system by S-ketamine, vortioxetine, and fluoxetine in a genetic rat model of depression.

PubMed

du Jardin, Kristian Gaarn; Liebenberg, Nico; Müller, Heidi Kaastrup; Elfving, Betina; Sanchez, Connie; Wegener, Gregers

2016-07-01

The mechanisms mediating ketamine's antidepressant effect have only been partly resolved. Recent preclinical reports implicate serotonin (5-hydroxytryptamine; 5-HT) in the antidepressant-like action of ketamine. Vortioxetine is a multimodal-acting antidepressant that is hypothesized to exert its therapeutic activity through 5-HT reuptake inhibition and modulation of several 5-HT receptors. The objective of this study was to evaluate the therapeutic-like profiles of S-ketamine, vortioxetine, and the serotonin reuptake inhibitor fluoxetine in response to manipulation of 5-HT tone. Flinders Sensitive Line (FSL) rats, a genetic model of depression, were depleted of 5-HT by repeated administration of 4-chloro-DL-phenylalanine methyl ester HCl (pCPA). Using pCPA-pretreated and control FSL rats, we investigated the acute and sustained effects of S-ketamine (15 mg/kg), fluoxetine (10 mg/kg), or vortioxetine (10 mg/kg) on recognition memory and depression-like behavior in the object recognition task (ORT) and forced swim test (FST), respectively. The behavioral phenotype of FSL rats was unaffected by 5-HT depletion. Vortioxetine, but not fluoxetine or S-ketamine, acutely ameliorated the memory deficits of FSL rats in the ORT irrespective of 5-HT tone. No sustained effects were observed in the ORT. In the FST, all three drugs demonstrated acute antidepressant-like activity but only S-ketamine had sustained effects. Unlike vortioxetine, the antidepressant-like responses of fluoxetine and S-ketamine were abolished by 5-HT depletion. These observations suggest that the acute and sustained antidepressant-like effects of S-ketamine depend on endogenous stimulation of 5-HT receptors. In contrast, the acute therapeutic-like effects of vortioxetine on memory and depression-like behavior may be mediated by direct activity at 5-HT receptors.
Regulation of emotional response in juvenile monkeys treated with fluoxetine: MAOA interactions

PubMed Central

Golub, M. S.; Phi, C. E.; Bulleri, A. M.

2016-01-01

Juvenile male rhesus macaques received therapeutic doses of fluoxetine daily from one to three years of age and were compared to vehicle-treated controls (N=16/group). Genotyping for monoamine oxidase A (MAOA) polymorphisms was used to form subgroups (N=8) with high and low expression of the gene. Behavioral responses were scored during 30-second exposures to pictures differing in affective content. As expected from its therapeutic effect, fluoxetine decreased the behavioral response to emotionally evocative pictures. A 44% reduction in number of expressive behaviors was seen, but only in subjects with low expression MAOA polymorphisms. In general, this effect occurred for pictures of varying affective content and was not due to altered occurrence of one specific behavior or type of behavior. The drug*genotype interaction was seen after one and two years of treatment and did not reverse one year after discontinuation of dosing. Two potential translational implications are suggested: (1) MAOA genetic polymorphisms may be the source of some of the variability in response to fluoxetine treatment in children; (2) extended fluoxetine treatment during juvenile brain development may result in persistent effects on emotional regulation. PMID:27852517
Fluoxetine signature on hippocampal MAPK signalling in sex-dependent manner.

PubMed

Mitic, Milos; Lukic, Iva; Bozovic, Natalija; Djordjevic, Jelena; Adzic, Miroslav

2015-02-01

A growing body of evidence indicates that mitogen-activated protein kinase (MAPK) participates in various stress-induced responses and is considered to be one of the pathophysiological mechanisms in depression. Surprisingly, the effect of antidepressants on MAPKs is almost unexplored, particularly from the perspective of sexes. The present study investigates the cytoplasm-nuclear distribution of MAPK family, c-Jun N-terminal kinases (JNKs) 1, 2 and 3; extracellular signal-regulated kinases (ERKs) 1 and 2; and p38 kinases, as well as their phosphoisoforms in the hippocampus of chronically stressed female and male rats and upon chronic fluoxetine treatment. Additionally, we analysed crosstalk between MAPK signalling and depressive-like behaviour which correlated with brain-derived neurotrophic factor (BDNF) expression. Our results emphasize a gender-specific and compartment-dependent response of MAPKs to stress and fluoxetine. In females, stress decreased pp38 and pJNK and induced cytosolic retention of pERKs which reduced all nuclear pMAPKs. These changes correlated with altered BDNF expression and behaviour. Similarly, in males, stress decreased pp38 but promoted nuclear translocation of pJNKs and pERKs. These stress alterations of pMAPKs in males were not associated with BDNF expression and depressive-like behaviour. Fluoxetine treatment in stressed females upregulated whole pMAPK signalling particularly those in nucleus which was followed with BDNF expression and normalization of behaviour. In stressed males, fluoxetine affected only cytosolic pJNKs, while nuclear pMAPK signalling and BDNF expression were unaffected even though fluoxetine normalized behaviour. Overall, our results suggest existence of gender-specific mechanism of fluoxetine on nuclear pMAPK/BDNF signalling and depressive-like behaviour and reinforce the antidepressant dogma that females and males respond differently to certain antidepressants.

Comparable efficacy and safety of 8 weeks treatment with agomelatine 25-50mg or fluoxetine 20-40mg in Asian out-patients with major depressive disorder.

PubMed

Shu, L; Sulaiman, A H; Huang, Y S; Fones Soon Leng, C; Crutel, V Strijckmans; Kim, Y S

2014-04-01

This randomized, double-blind study evaluates the efficacy and tolerability of agomelatine, using fluoxetine as an active comparator, in Asian patients suffering from moderate to severe major depressive disorder (MDD). Patients were randomly assigned to receive either agomelatine (25-50mg/day, n=314) or fluoxetine (20-40mg/day, n=314) during an 8-week treatment period. The main outcome measure was the change in Hamilton Depression Rating Scale 17 items (HAM-D17) scores. Secondary efficacy criteria included scores on Clinical Global Impression Severity of illness (CGI-S) and Improvement of illness (CGI-I), patient sleeping improvement using the self-rating Leeds Sleep Evaluation Questionnaire (LSEQ) and anxiety using the Hamilton Anxiety Rating Scale (HAM-A) scores. Tolerability and safety evaluations were based on emergent adverse events. Agomelatine and fluoxetine exert a comparable antidepressant efficacy in the Asian population. Mean changes over 8 weeks were clinically relevant and similar in both groups (-14.8±7.3 and -15.0±8.1 on HAM-D17 scale in agomelatine and fluoxetine groups, respectively). The between-group difference reached statistical significance on non-inferiority test (p=0.015). Clinically relevant decreases in CGI-S and CGI-I scores were observed over the treatment period in both groups. The two treatments were equally effective on the symptoms of both anxiety and sleep. The good tolerability profile and safety of both doses of agomelatine was confirmed in the Asian population. Agomelatine and fluoxetine are equally effective in the treatment of MDD-associated symptoms in Asian depressed patients. Copyright © 2013 Elsevier B.V. All rights reserved.
Fluoxetine disrupts motivation and GABAergic signaling in adolescent female hamsters.

PubMed

Shannonhouse, John L; DuBois, Dustin W; Fincher, Annette S; Vela, Alejandra M; Henry, Morgan M; Wellman, Paul J; Frye, Gerald D; Morgan, Caurnel

2016-08-01

Initial antidepressant treatment can paradoxically worsen symptoms in depressed adolescents by undetermined mechanisms. Interestingly, antidepressants modulate GABAA receptors, which mediate paradoxical effects of other therapeutic drugs, particularly in females. Although the neuroanatomic site of action for this paradox is unknown, elevated GABAA receptor signaling in the nucleus accumbens can disrupt motivation. We assessed fluoxetine's effects on motivated behaviors in pubescent female hamsters - anhedonia in the reward investigational preference (RIP) test as well as anxiety in the anxiety-related feeding/exploration conflict (AFEC) test. We also assessed accumbal signaling by RT-PCR and electrophysiology. Fluoxetine initially worsened motivated behaviors at puberty, relative to adulthood. It also failed to improve these behaviors as pubescent hamsters transitioned into adulthood. Low accumbal mRNA levels of multiple GABAA receptor subunits and GABA-synthesizing enzyme, GAD67, assessed by RT-PCR, suggested low GABAergic tone at puberty. Nonetheless, rapid fluoxetine-induced reductions of α5GABAA receptor and BDNF mRNA levels at puberty were consistent with age-related differences in GABAergic responses to fluoxetine and disruption of the motivational state. Whole-cell patch clamping of accumbal slices also suggested low GABAergic tone by the low amplitude of miniature inhibitory postsynaptic currents (mIPSCs) at puberty. It also confirmed age-related differences in GABAergic responses to fluoxetine. Specifically, fluoxetine potentiated mIPSC amplitude and frequency at puberty, but attenuated the amplitude during adulthood. These results implicate GABAergic tone and GABAA receptor plasticity in adverse motivational responses and resistance to fluoxetine during adolescence. Copyright © 2016 Elsevier Inc. All rights reserved.
Long-term Ameliorative Effects of the Antidepressant Fluoxetine Exposure on Cognitive Deficits in 3 × TgAD Mice.

PubMed

Jin, Li; Gao, Li-Feng; Sun, Dong-Sheng; Wu, Hao; Wang, Qun; Ke, Dan; Lei, Hao; Wang, Jian-Zhi; Liu, Gong-Ping

2017-08-01

Fluoxetine, a selective serotonin reuptake inhibitor, is neuroprotective; therefore, it has been applied to treat some neurodegenerative disorders. For instance, chronic fluoxetine exposure has short-term effects on Alzheimer's disease (AD). However, the long-term ameliorative effects of fluoxetine exposure on AD have not been reported. In the present study, 6-month-old 3 × TgAD mice were treated with fluoxetine for 15 days, and then the influence of fluoxetine was detected at 20 days after the drug withdrawal. We found that chronic fluoxetine treatment ameliorated cognitive deficits of 3 × TgAD mice and increased the volume of the hippocampal CA1 and dentate gyrus (DG) with increased neuron number and dendritic spine density. Meanwhile, fluoxetine exposure also stimulated the long-term potentiation (LTP) in hippocampal DG. The synaptic-related protein expression increased via activation of the cyclic AMP response element binding (CREB) protein/brain-derived neurotrophic factor (BDNF) signaling pathway induced by fluoxetine exposure. Lastly, we found that fluoxetine treatment decreased beta-amyloid (Aβ) levels. These results further certified that fluoxetine may be a potent effective drug for AD.
Effects of Fluoxetine on Neural Functional Prognosis after Ischemic Stroke: A Randomized Controlled Study in China.

PubMed

He, Yi-Tao; Tang, Bing-Shan; Cai, Zhi-Li; Zeng, Si-Ling; Jiang, Xin; Guo, Yi

2016-04-01

We investigated the effects of fluoxetine on the short-term and long-term neural functional prognoses after ischemic stroke. In this prospective randomized controlled single-blind clinical study in China, eligible patients afflicted with ischemic stroke were randomized into control and treatment groups. Patients in the treatment group received fluoxetine in addition to the basic therapies in the control group over a period of 90 days. The follow-up period was 180 days. We evaluated the effects of fluoxetine on the National Institutes of Health Stroke Scale (NIHSS) score and Barthel Index (BI) score after ischemic stroke through single- and multiple-factor analysis. The mean NIHSS score on day 180 after treatment was significantly lower in the treatment group than in the control group (P = .009). The mean BI scores on days 90 and 180 were significantly higher in the treatment group (P = .026) than in the control group (P = .011). The improvements in the NIHSS and BI scores on days 90 and 180 compared with baseline in the treatment group were all significantly greater than that in the control group (P = .033, P = .013, P = .013, P = .019, respectively). Treatment with fluoxetine was an independent factor affecting the NIHSS and BI scores on day 180 after treatment. Treatment with fluoxetine for 90 days after ischemic stroke can improve the long-term neural functional outcomes. Copyright © 2016 National Stroke Association. Published by Elsevier Inc. All rights reserved.
Short-term fluoxetine treatment induces neuroendocrine and behavioral anxiogenic-like responses in adolescent male rats.

PubMed

Gomez, Francisca; Venero, César; Viveros, María-Paz; García-García, Luis

2015-03-01

Fluoxetine (FLX) is prescribed to treat depression and anxiety in adolescent patients. However, FLX has anxiogenic effects during the acute phase of treatment, and caution has been raised due to increased suicidal thinking and behavior. Herein, we sought to study in adolescent (35-day-old) male rats, the effects of short-term FLX treatment (10 mg/kg/day, i.p. for 3-4 days) on hypothalamic-pituitary-adrenal axis activity, serotonin (5-hidroxytriptamine, 5-HT) transporter (SERT) mRNA expression in the dorsal raphe nucleus (DRN), energy balance-related variables and behavioral profiles in the holeboard. Our results revealed that daily FLX administration increased plasma corticosterone (B) concentrations without affecting basal gene expression of corticotrophin releasing hormone in the hypothalamic paraventricular nucleus (PVN) nor of pro-opiomelanocortin in the anterior pituitary. However, FLX had significant effects increasing the mRNA expression of PVN arginine vasopressin (AVP) and reducing SERT mRNA levels in the dorsolateral subdivision of the DRN. In the holeboard, FLX-induced anxiety/emotionality-like behaviors. As expected, FLX treatment was endowed with anorectic effects and reduced body weight gain. Altogether, our study shows that short-term FLX treatment results in physiological, neuroendocrine and behavioral stress-like effects in adolescent male rats. More importantly, considering that the AVP- and 5-HTergic systems: (1) are intimately involved in regulation of the stress response; (2) are regulated by sex hormones and (3) are related to regulation of aggressive behaviors, our results highlight the potential significance of these systems mediating the anxiogenic/emotionality/stress-like responses of adolescent male rats to short-term FLX treatment.
Pharmacogenetic study focused on fluoxetine pharmacodynamics in children and adolescent patients: impact of the serotonin pathway.

PubMed

Mas, Sergi; Blázquez, Ana; Rodríguez, Natalia; Boloc, Daniel; Lafuente, Amalia; Arnaiz, Joan A; Lázaro, Luisa; Gassó, Patricia

2016-11-01

Pharmacogenetic studies of fluoxetine in children and adolescents are scarce. After reporting the effect of genetic variants in genes related to the fluoxetine pharmacokinetics on clinical response in a pediatric population, we now evaluate the impact of genetic markers involved in its pharmacodynamics. The assessment was performed in 83 patients after 12 weeks of fluoxetine treatment. The genetic association analysis included a total of 316 validated single nucleotide polymorphisms in 45 candidate genes involved in six different pathways. Clinical improvement after treatment with fluoxetine in our pediatric population was associated significantly with two polymorphisms located in genes related to the serotonergic system: the 5-hydroxytryptamine receptor 1B (HTR1B) and the tryptophan 5-hydroxylase 2 (TPH2). Although a wide range of candidate genes related to different pathways were assessed, the results show that genetic markers directly related to serotonin have an important effect on fluoxetine response.
The antidepressant fluoxetine induces necrosis by energy depletion and mitochondrial calcium overload.

PubMed

Charles, Emilie; Hammadi, Mehdi; Kischel, Philippe; Delcroix, Vanessa; Demaurex, Nicolas; Castelbou, Cyril; Vacher, Anne-Marie; Devin, Anne; Ducret, Thomas; Nunes, Paula; Vacher, Pierre

2017-01-10

Selective Serotonin Reuptake Inhibitor antidepressants, such as fluoxetine (Prozac), have been shown to induce cell death in cancer cells, paving the way for their potential use as cancer therapy. These compounds are able to increase cytosolic calcium concentration ([Ca2+]cyt), but the involved mechanisms and their physiological consequences are still not well understood. Here, we show that fluoxetine induces an increase in [Ca2+]cyt by emptying the endoplasmic reticulum (ER) through the translocon, an ER Ca2+ leakage structure. Our data also show that fluoxetine inhibits oxygen consumption and lowers mitochondrial ATP. This latter is essential for Ca2+ reuptake into the ER, and we postulated therefore that the fluoxetine-induced decrease in mitochondrial ATP production results in the emptying of the ER, leading to capacitative calcium entry. Furthermore, Ca2+ quickly accumulated in the mitochondria, leading to mitochondrial Ca2+ overload and cell death. We found that fluoxetine could induce an early necrosis in human peripheral blood lymphocytes and Jurkat cells, and could also induce late apoptosis, especially in the tumor cell line. These results shed light on fluoxetine-induced cell death and its potential use in cancer treatment.
The antidepressant fluoxetine induces necrosis by energy depletion and mitochondrial calcium overload

PubMed Central

Kischel, Philippe; Delcroix, Vanessa; Demaurex, Nicolas; Castelbou, Cyril; Vacher, Anne-Marie; Devin, Anne; Ducret, Thomas; Nunes, Paula; Vacher, Pierre

2017-01-01

Selective Serotonin Reuptake Inhibitor antidepressants, such as fluoxetine (Prozac), have been shown to induce cell death in cancer cells, paving the way for their potential use as cancer therapy. These compounds are able to increase cytosolic calcium concentration ([Ca2+]cyt), but the involved mechanisms and their physiological consequences are still not well understood. Here, we show that fluoxetine induces an increase in [Ca2+]cyt by emptying the endoplasmic reticulum (ER) through the translocon, an ER Ca2+ leakage structure. Our data also show that fluoxetine inhibits oxygen consumption and lowers mitochondrial ATP. This latter is essential for Ca2+ reuptake into the ER, and we postulated therefore that the fluoxetine-induced decrease in mitochondrial ATP production results in the emptying of the ER, leading to capacitative calcium entry. Furthermore, Ca2+ quickly accumulated in the mitochondria, leading to mitochondrial Ca2+ overload and cell death. We found that fluoxetine could induce an early necrosis in human peripheral blood lymphocytes and Jurkat cells, and could also induce late apoptosis, especially in the tumor cell line. These results shed light on fluoxetine-induced cell death and its potential use in cancer treatment. PMID:27911858
A chronic treatment with fluoxetine decreases 5-HT(1A) receptors labeling in mice selected as a genetic model of helplessness.

PubMed

Naudon, Laurent; El Yacoubi, Malika; Vaugeois, Jean-Marie; Leroux-Nicollet, Isabelle; Costentin, Jean

2002-05-17

Two lines of mice were bred for their opposite helpless behavior in the tail suspension test, i.e., helpless (HL) mice and non helpless (NHL) mice. The 5-HT(1A) receptor labeling was quantified by means of autoradiography with (3)H-8-OH-DPAT on brain sections from mice of these two lines. We observed a significantly higher level of (3)H-8-OH-DPAT binding sites density in HL mice comparatively to NHL mice, in the medial prefrontal, cingulate, motor and sensorial cortices, in several regions of the limbic system, such as CA3 field of hippocampus, dentate gyrus, medial and baso-medial amygdala, and in dorsal and median raphe nuclei. A chronic 21-day treatment with the antidepressant fluoxetine (10 mg/kg, i.p. daily) attenuated significantly the spontaneous helplessness in HL mice but did not alter the behavior of NHL mice. In the brain of HL mice chronically injected with fluoxetine, the elevated (3)H-8-OH-DPAT binding sites density was no longer observed after treatment in several regions, among which the raphe nuclei. Conversely, the antidepressant treatment did not modify the (3)H-8-OH-DPAT binding sites density in NHL mice. The variation of 5-HT(1A) receptors binding density in the HL mice in response to a chronic fluoxetine treatment parallels the attenuation of the spontaneous helplessness observed in the tail suspension test, and may underlie this behavior.
Regulation of emotional response in juvenile monkeys treated with fluoxetine: MAOA interactions.

PubMed

Golub, M S; Hogrefe, C E; Bulleri, A M

2016-12-01

Juvenile male rhesus macaques received therapeutic doses of fluoxetine daily from one to three years of age and were compared to vehicle-treated controls (N=16/group). Genotyping for monoamine oxidase A (MAOA) polymorphisms was used to form subgroups (N=8) with high and low expression of the gene. Behavioral responses were scored during 30-second exposures to pictures differing in affective content. As expected from its therapeutic effect, fluoxetine decreased the behavioral response to emotionally evocative pictures. A 44% reduction in number of expressive behaviors was seen, but only in subjects with low expression MAOA polymorphisms. In general, this effect occurred for pictures of varying affective content and was not due to altered occurrence of one specific behavior or type of behavior. The drug*genotype interaction was seen after one and two years of treatment and did not reverse one year after discontinuation of dosing. Two potential translational implications are suggested: (1) MAOA genetic polymorphisms may be the source of some of the variability in response to fluoxetine treatment in children; (2) extended fluoxetine treatment during juvenile brain development may result in persistent effects on emotional regulation. Copyright Â© 2016 Elsevier B.V. and ECNP. All rights reserved.
Toxicokinetics, disposition and metabolism of fluoxetine in crabs.

PubMed

Robert, Alexandrine; Schultz, Irvin R; Hucher, Nicolas; Monsinjon, Tiphaine; Knigge, Thomas

2017-11-01

The disposition and metabolism of fluoxetine in the European shore crab and the Dungeness crab were assessed. Crabs received intracardiac doses of either 0.13 μg/kg or 0.5 mg/kg fluoxetine, respectively. In addition, fluoxetine was administered to Metacarcinus cancer by oral gavage at 7.8 mg/kg. The distribution of fluoxetine was quantified in haemolymph and digestive gland for both crabs, as well as brain, muscle, and testis of Carcinus maenas, over 12 days. The metabolite norfluoxetine, was also measured in C. maenas. Fluoxetine was mainly found in lipid rich tissues. Distribution coefficients increased for digestive gland until three days after fluoxetine administration and then decreased until the end of the observations. The highest distribution coefficients were obtained for brain. Norfluoxetine displayed continuously high levels in digestive gland and brain. The strong decrease in fluoxetine and the concomitant increase in norfluoxetine demonstrates that decapod crustaceans metabolise fluoxetine into the more biologically active norfluoxetine. Fluoxetine levels in the haemolymph of M. cancer declined within 20 h, but showed a second peak 25 h later, suggesting remobilisation from tissues sequestering the compound. The steady state volume distribution and the total body clearance of fluoxetine were high, consistent with high diffusion of fluoxetine into the peripheral tissues and biotransformation as an important elimination pathway. Oral administration of fluoxetine prolonged its half-life in M. cancer, but bioavailability was low. These results confirm the high distribution into nervous tissue, extensive biotransformation into the highly active norfluoxetine and a half-life similar to that observed in vertebrates. Copyright © 2017 Elsevier Ltd. All rights reserved.
Fluoxetine potentiation of omega-3 fatty acid antidepressant effect: evaluating pharmacokinetic and brain fatty acid-related aspects in rodents.

PubMed

Laino, Carlos Horacio; Garcia, Pilar; Podestá, María Fernanda; Höcht, Christian; Slobodianik, Nora; Reinés, Analía

2014-10-01

We previously reported that combined fluoxetine administration at antidepressant doses renders additive antidepressant effects, whereas non-antidepressant doses potentiate the omega-3 fatty acid antidepressant effect. In the present study, we aimed to evaluate putative pharmacokinetic and brain omega-3 fatty acid-related aspects for fluoxetine potentiation of omega-3 fatty acid antidepressant effect in rats. Coadministration of omega-3 fatty acids with a non-antidepressant dose of fluoxetine (1 mg/kg day) failed to affect both brain fluoxetine concentration and norfluoxetine plasma concentration profile. Fluoxetine plasma concentrations remained below the sensitivity limit of the detection method. Either antidepressant (10 mg/kg day) or non-antidepressant (1 mg/kg day) doses of fluoxetine in combination with omega-3 fatty acids increased hippocampal docosapentaenoic acid (DPA, 22:5 omega-3) levels. Although individual treatments had no effects on DPA concentration, DPA increase was higher when omega-3 were combined with the non-antidepressant dose of fluoxetine. Chronic DPA administration exerted antidepressant-like effects in the forced swimming test while increasing hippocampal docosahexaenoic (22:6 omega-3) and DPA levels. Our results suggest no pharmacokinetic interaction and reveal specific hippocampal DPA changes after fluoxetine and omega-3 combined treatments in our experimental conditions. The DPA role in the synergistic effect of fluoxetine and omega-3 combined treatments will be for sure the focus of future studies. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 103:3316-3325, 2014. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association.
Fluoxetine prevents the memory deficits and reduction in hippocampal cell proliferation caused by valproic acid.

PubMed

Welbat, Jariya Umka; Sangrich, Preeyanuch; Sirichoat, Apiwat; Chaisawang, Pornthip; Chaijaroonkhanarak, Wunnee; Prachaney, Parichat; Pannangrong, Wanassanun; Wigmore, Peter

2016-12-01

Valproic acid (VPA), a commonly used antiepileptic drug, has been reported to cause cognitive impairments in patients. In a previous study, using a rodent model, we showed that VPA treatment impaired cognition which was associated with a reduction in the cell proliferation required for hippocampal neurogenesis. The antidepressant fluoxetine has been shown to increase hippocampal neurogenesis and to reverse the memory deficits found in a number of pathological conditions. In the present study we investigated the protective effects of fluoxetine treatment against the impairments in memory and hippocampal cell proliferation produced by VPA. Male Sprague Dawley rats received daily treatment with fluoxetine (10mg/kg) by oral gavage for 21days. Some rats were co-administered with VPA (300mg/kg, twice daily i.p. injections) for 14days from day 8 to day 21 of the fluoxetine treatment. Spatial memory was tested using the novel object location (NOL) test. The number of proliferating cells present in the sub granular zone of the dentate gyrus was quantified using Ki67 immunohistochemistry at the end of the experiment. Levels of the receptor Notch1, the neurotrophic factor BDNF and the neural differentiation marker DCX were determined by Western blotting. VPA-treated rats showed memory deficits, a decrease in the number of proliferating cells in the sub granular zone and decreases in the levels of Notch1 and BDNF but not DCX compared to control animals. These changes in behavior, cell proliferation and Notch1 and BDNF were prevented in animals which had received both VPA and fluoxetine. Rats receiving fluoxetine alone did not show a significant difference in the number of proliferating cells or behavior compared to controls. These results demonstrated that the spatial memory deficits and reduction of cell proliferation produced by VPA can be ameliorated by the simultaneous administration of the antidepressant fluoxetine. Crown Copyright Â© 2016. Published by Elsevier B
Acute SSRI-induced anxiogenic and brain metabolic effects are attenuated 6 months after initial MDMA-induced depletion.

PubMed

Andó, Rómeó D; Adori, Csaba; Kirilly, Eszter; Molnár, Eszter; Kovács, Gábor G; Ferrington, Linda; Kelly, Paul A T; Bagdy, György

2010-03-05

To assess the functional state of the serotonergic system, the acute behavioural and brain metabolic effect of SSRI antidepressants were studied during the recovery period after MDMA-induced neuronal damage. The effects of the SSRI fluoxetine and the serotonin receptor agonist meta-chloro-phenylpiperazine (m-CPP) were investigated in the social interaction test in Dark Agouti rats, 6 months after treatment with a single dose of MDMA (15 or 30 mg kg(-1), i.p.). At earlier time points these doses of MDMA have been shown to cause 30-60% loss in axonal densities in several brain regions. Densities of the serotonergic axons were assessed using serotonin-transporter and tryptophan-hydroxylase immunohistochemistry. In a parallel group of animals, brain function was examined following an acute challenge with either fluoxetine or citalopram, using 2-deoxyglucose autoradiographic imaging. Six months after MDMA treatment the densities of serotonergic axons were decreased in only a few brain areas including hippocampus and thalamus. Basal anxiety was unaltered in MDMA-treated animals. However, the acute anxiogenic effects of fluoxetine, but not m-CPP, were attenuated in animals pretreated with MDMA. The metabolic response to both citalopram and fluoxetine was normal in most of the brain areas examined with the exception of ventromedial thalamus and hippocampal sub-fields where the response was attenuated. These data provide evidence that 6 months after MDMA-induced damage serotonergic axons show recovery in most brain areas, but serotonergic functions to challenges with SSRIs including anxiety and aggression remain altered. Copyright 2009 Elsevier B.V. All rights reserved.
Peer social interaction is facilitated in juvenile rhesus monkeys treated with fluoxetine.

PubMed

Golub, Mari S; Hogrefe, Casey E; Bulleri, Alicia M

2016-06-01

Fluoxetine improves social interactions in children with autism, social anxiety and social phobia. It is not known whether this effect is mediated directly or indirectly by correcting the underlying pathology. Genetics may also influence the drug effect. Polymorphisms of the MAOA (monoamine oxidase A) gene interact with fluoxetine to influence metabolic profiles in juvenile monkeys. Juvenile nonhuman primates provide an appropriate model for studying fluoxetine effects and drug*gene interactions in children. Male rhesus monkeys 1-3 years of age living in permanent social pairs were treated daily with a therapeutic dose of fluoxetine or vehicle (n = 16/group). Both members of each social pair were assigned to the same treatment group. They were observed for social interactions with their familiar cagemate over a 2-year dosing period. Subjects were genotyped for MAOA variable number of tandem repeats (VNTR) polymorphisms categorized for high or low transcription rates (hi-MAOA, low-MAOA). Fluoxetine-treated animals spent 30% more time in social interaction than vehicle controls. Fluoxetine significantly increased the duration of quiet interactions, the most common type of interaction, and also of immature sexual behavior typical of rhesus in this age group. Specific behaviors affected depended on MAOA genotype of the animal and its social partner. When given fluoxetine, hi-MOAO monkeys had more social invitation and initiation behaviors and low-MAOA subjects with low-MAOA partners had more grooming and an increased frequency of some facial and vocal expressive behaviors. Fluoxetine may facilitate social interaction in children independent of remediation of psychopathology. Common genetic variants may modify this effect. Copyright © 2016 Elsevier Ltd. All rights reserved.
Peer social interaction is facilitated in juvenile rhesus monkeys treated with fluoxetine

PubMed Central

Golub, Mari S.; Hogrefe, Casey E.; Bulleri, Alicia M.

2016-01-01

Background Fluoxetine improves social interactions in children with autism, social anxiety and social phobia. It is not known whether this effect is mediated directly or indirectly by correcting the underlying pathology. Genetics may also influence the drug effect. Polymorphisms of the MAOA (monoamine oxidase A) gene interact with fluoxetine to influence metabolic profiles in juvenile monkeys. Juvenile nonhuman primates provide an appropriate model for studying fluoxetine effects and drug*gene interactions in children. Methods Male rhesus monkeys 1–3 years of age living in permanent social pairs were treated daily with a therapeutic dose of fluoxetine or vehicle (n=16/group). Both members of each social pair were assigned to the same treatment group. They were observed for social interactions with their familiar cagemate over a 2-year dosing period. Subjects were genotyped for MAOA variable number of tandem repeats (VNTR) polymorphisms categorized for high or low transcription rates (hi-MAOA, low-MAOA). Results Fluoxetine-treated animals spent 30% more time in social interaction than vehicle controls. Fluoxetine significantly increased the duration of quiet interactions, the most common type of interaction, and also of immature sexual behavior typical of rhesus in this age group. Specific behaviors affected depended on MAOA genotype of the animal and its social partner. When given fluoxetine, hi-MOAO monkeys had more social invitations and initiation behaviors and low-MAOA subjects with low-MAOA partners had more grooming and an increased frequency of some facial and vocal expressive behaviors. Conclusions Fluoxetine may facilitate social interaction in children independent of remediation of psychopathology. Common genetic variants may modify this effect. PMID:26905291
Fluoxetine-treated male wrasses exhibit low AVT expression.

PubMed

Semsar, Katharine; Perreault, Heidi A N; Godwin, John

2004-12-17

In many species, increasing serotonergic activity can reduce aggression and reverse dominance relationships. These effects may in part be mediated through interactions with the arginine vasotocin/vasopressin (AVT/AVP) system. We tested this hypothesis in a territorial coral reef fish, the bluehead wrasse (Thalassoma bifasciatum), by experimentally enhancing serotonergic neurotransmission, using the selective serotonin re-uptake inhibitor (SSRI) fluoxetine. Terminal phase (TP) males received 2 weeks of nightly intraperitoneal fluoxetine injections (6 microg/g body weight) and were then tested for their aggressive response to an intruder and killed to examine AVT phenotype in the preoptic area of the hypothalamus (POA), an area important to social behavior in fishes. Our previously published study demonstrated that fluoxetine-treated males are less aggressive [H.A.N. Perreault, K. Semsar, J. Godwin, Fluoxetine treatment decreases territorial aggression in a coral reef fish, Physiol. and Behav. 79 (2003) 719-724.]. Here, further study of these same fluoxetine-treated males shows approximately twofold lower AVT mRNA expression relative to saline-treated controls in all regions of the POA (all p< or =0.05) without any changes in AVT-ir soma size (all p>0.4). This study experimentally supports the hypothesis that behavioral effects of SSRIs may be mediated in part through interactions with the AVT/AVP system. These results parallel findings from rodents and humans and are consistent with an indirect neurosteroidogenic rather than a solely direct serotonergic mechanism for SSRI effects on the AVT/AVP system. Furthermore, they suggest that SSRI effects on neuroendocrine function may be best modeled in animals with sensitive stress responses such as those found in nondomesticated animals.
Fluoxetine increases plasticity and modulates the proteomic profile in the adult mouse visual cortex

PubMed Central

Ruiz-Perera, L.; Muniz, M.; Vierci, G.; Bornia, N.; Baroncelli, L.; Sale, A.; Rossi, F.M.

2015-01-01

The scarce functional recovery of the adult CNS following injuries or diseases is largely due to its reduced potential for plasticity, the ability to reorganize neural connections as a function of experience. Recently, some new strategies restoring high levels of plasticity in the adult brain have been identified, especially in the paradigmatic model of the visual system. A chronic treatment with the anti-depressant fluoxetine reinstates plasticity in the adult rat primary visual cortex, inducing recovery of vision in amblyopic animals. The molecular mechanisms underlying this effect remain largely unknown. Here, we explored fluoxetine effects on mouse visual cortical plasticity, and exploited a proteomic approach to identify possible candidates mediating the outcome of the antidepressant treatment on adult cortical plasticity. We showed that fluoxetine restores ocular dominance plasticity in the adult mouse visual cortex, and identified 31 differentially expressed protein spots in fluoxetine-treated animals vs. controls. MALDITOF/TOF mass spectrometry identification followed by bioinformatics analysis revealed that these proteins are involved in the control of cytoskeleton organization, endocytosis, molecular transport, intracellular signaling, redox cellular state, metabolism and protein degradation. Altogether, these results indicate a complex effect of fluoxetine on neuronal signaling mechanisms potentially involved in restoring plasticity in the adult brain. PMID:26205348
Individualized homeopathic treatment and fluoxetine for moderate to severe depression in peri- and postmenopausal women (HOMDEP-MENOP study): a randomized, double-dummy, double-blind, placebo-controlled trial.

PubMed

Macías-Cortés, Emma Del Carmen; Llanes-González, Lidia; Aguilar-Faisal, Leopoldo; Asbun-Bojalil, Juan

2015-01-01

Perimenopausal period refers to the interval when women's menstrual cycles become irregular and is characterized by an increased risk of depression. Use of homeopathy to treat depression is widespread but there is a lack of clinical trials about its efficacy in depression in peri- and postmenopausal women. The aim of this study was to assess efficacy and safety of individualized homeopathic treatment versus placebo and fluoxetine versus placebo in peri- and postmenopausal women with moderate to severe depression. A randomized, placebo-controlled, double-blind, double-dummy, superiority, three-arm trial with a 6 week follow-up study was conducted. The study was performed in a public research hospital in Mexico City in the outpatient service of homeopathy. One hundred thirty-three peri- and postmenopausal women diagnosed with major depression according to DSM-IV (moderate to severe intensity) were included. The outcomes were: change in the mean total score among groups on the 17-item Hamilton Rating Scale for Depression, Beck Depression Inventory and Greene Scale, after 6 weeks of treatment, response and remission rates, and safety. Efficacy data were analyzed in the intention-to-treat population (ANOVA with Bonferroni post-hoc test). After a 6-week treatment, homeopathic group was more effective than placebo by 5 points in Hamilton Scale. Response rate was 54.5% and remission rate, 15.9%. There was a significant difference among groups in response rate definition only, but not in remission rate. Fluoxetine-placebo difference was 3.2 points. No differences were observed among groups in the Beck Depression Inventory. Homeopathic group was superior to placebo in Greene Climacteric Scale (8.6 points). Fluoxetine was not different from placebo in Greene Climacteric Scale. Homeopathy and fluoxetine are effective and safe antidepressants for climacteric women. Homeopathy and fluoxetine were significantly different from placebo in response definition only. Homeopathy, but
Individualized Homeopathic Treatment and Fluoxetine for Moderate to Severe Depression in Peri- and Postmenopausal Women (HOMDEP-MENOP Study): A Randomized, Double-Dummy, Double-Blind, Placebo-Controlled Trial

PubMed Central

Macías-Cortés, Emma del Carmen; Llanes-González, Lidia; Aguilar-Faisal, Leopoldo; Asbun-Bojalil, Juan

2015-01-01

Background Perimenopausal period refers to the interval when women's menstrual cycles become irregular and is characterized by an increased risk of depression. Use of homeopathy to treat depression is widespread but there is a lack of clinical trials about its efficacy in depression in peri- and postmenopausal women. The aim of this study was to assess efficacy and safety of individualized homeopathic treatment versus placebo and fluoxetine versus placebo in peri- and postmenopausal women with moderate to severe depression. Methods/Design A randomized, placebo-controlled, double-blind, double-dummy, superiority, three-arm trial with a 6 week follow-up study was conducted. The study was performed in a public research hospital in Mexico City in the outpatient service of homeopathy. One hundred thirty-three peri- and postmenopausal women diagnosed with major depression according to DSM-IV (moderate to severe intensity) were included. The outcomes were: change in the mean total score among groups on the 17-item Hamilton Rating Scale for Depression, Beck Depression Inventory and Greene Scale, after 6 weeks of treatment, response and remission rates, and safety. Efficacy data were analyzed in the intention-to-treat population (ANOVA with Bonferroni post-hoc test). Results After a 6-week treatment, homeopathic group was more effective than placebo by 5 points in Hamilton Scale. Response rate was 54.5% and remission rate, 15.9%. There was a significant difference among groups in response rate definition only, but not in remission rate. Fluoxetine-placebo difference was 3.2 points. No differences were observed among groups in the Beck Depression Inventory. Homeopathic group was superior to placebo in Greene Climacteric Scale (8.6 points). Fluoxetine was not different from placebo in Greene Climacteric Scale. Conclusion Homeopathy and fluoxetine are effective and safe antidepressants for climacteric women. Homeopathy and fluoxetine were significantly different from placebo

A double-blind, randomized, placebo-controlled trial of fluoxetine in patients with intermittent explosive disorder.

PubMed

Coccaro, Emil F; Lee, Royce J; Kavoussi, Richard J

2009-04-21

Intermittent explosive disorder (IED) is a disorder of impulsive aggression that affects as many as 7.3% of the U.S. population during some period of life. Since central serotonergic (5-HT) system dysfunction is related to impulsive aggressive behavior, pharmacologic enhancement of 5-HT activity should reduce impulsive aggressive behavior in individuals with IED. A double-blind, randomized, placebo-controlled trial of the selective 5-HT uptake inhibitor fluoxetine was conducted in 100 individuals with IED (research diagnostic criteria) and current histories of impulsive aggressive behavior. The primary efficacy measure was the aggression score from the Overt Aggression Scale-Modified (OAS-M) for Outpatient Use. Secondary efficacy measures included the irritability score from the OAS-M and the Clinical Global Impressions-Improvement scale (CGI-I) score. The study took place between July 1990 and July 1999. Fluoxetine treatment resulted in a sustained reduction in OAS-M aggression, and OAS-M irritability scores, apparent as early as week 2 (p < .01 for aggression and p < .001 for irritability at endpoint). Fluoxetine was also superior to placebo in the proportion of responders on the CGI-I (p < .001). Closer examination of the data revealed that full or partial remission of impulsive aggressive behaviors, as reflected by the A criteria for IED, occurred in 46% of fluoxetine-treated subjects. Fluoxetine did not exert an antidepressant or antianxiety effect, and its effects on impulsive aggression were not influenced by presence of current symptoms of depression or anxiety. Fluoxetine treatment has a clear antiaggressive effect in impulsive aggressive individuals with IED. However, while fluoxetine's antiaggressive effects appear robust, they lead to full or partial remission of IED in less than 50% of subjects treated with fluoxetine. Copyright 2009 Physicians Postgraduate Press, Inc.
Differential induction of FosB isoforms throughout the brain by fluoxetine and chronic stress.

PubMed

Vialou, Vincent; Thibault, Mackenzie; Kaska, Sophia; Cooper, Sarah; Gajewski, Paula; Eagle, Andrew; Mazei-Robison, Michelle; Nestler, Eric J; Robison, A J

2015-12-01

Major depressive disorder is thought to arise in part from dysfunction of the brain's "reward circuitry", consisting of the mesolimbic dopamine system and the glutamatergic and neuromodulatory inputs onto this system. Both chronic stress and antidepressant treatment regulate gene transcription in many of the brain regions that make up these circuits, but the exact nature of the transcription factors and target genes involved in these processes remain unclear. Here, we demonstrate induction of the FosB family of transcription factors in ∼25 distinct regions of adult mouse brain, including many parts of the reward circuitry, by chronic exposure to the antidepressant fluoxetine. We further uncover specific patterns of FosB gene product expression (i.e., differential expression of full-length FosB, ΔFosB, and Δ2ΔFosB) in brain regions associated with depression--the nucleus accumbens (NAc), prefrontal cortex (PFC), and hippocampus--in response to chronic fluoxetine treatment, and contrast these patterns with differential induction of FosB isoforms in the chronic social defeat stress model of depression with and without fluoxetine treatment. We find that chronic fluoxetine, in contrast to stress, causes induction of the unstable full-length FosB isoform in the NAc, PFC, and hippocampus even 24 h following the final injection, indicating that these brain regions may undergo chronic activation when fluoxetine is on board, even in the absence of stress. We also find that only the stable ΔFosB isoform correlates with behavioral responses to stress. These data suggest that NAc, PFC, and hippocampus may present useful targets for directed intervention in mood disorders (ie, brain stimulation or gene therapy), and that determining the gene targets of FosB-mediated transcription in these brain regions in response to fluoxetine may yield novel inroads for pharmaceutical intervention in depressive disorders. Copyright © 2015 Elsevier Ltd. All rights reserved.
21 CFR 520.980 - Fluoxetine.

Code of Federal Regulations, 2012 CFR

2012-04-01

... 21 Food and Drugs 6 2012-04-01 2012-04-01 false Fluoxetine. 520.980 Section 520.980 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) ANIMAL DRUGS, FEEDS, AND RELATED PRODUCTS ORAL DOSAGE FORM NEW ANIMAL DRUGS § 520.980 Fluoxetine. (a) Specifications. Each...
1H NMR-based metabolic profiling reveals the effects of fluoxetine on lipid and amino acid metabolism in astrocytes.

PubMed

Bai, Shunjie; Zhou, Chanjuan; Cheng, Pengfei; Fu, Yuying; Fang, Liang; Huang, Wen; Yu, Jia; Shao, Weihua; Wang, Xinfa; Liu, Meiling; Zhou, Jingjing; Xie, Peng

2015-04-15

Fluoxetine, a selective serotonin reuptake inhibitor (SSRI), is a prescribed and effective antidepressant and generally used for the treatment of depression. Previous studies have revealed that the antidepressant mechanism of fluoxetine was related to astrocytes. However, the therapeutic mechanism underlying its mode of action in astrocytes remains largely unclear. In this study, primary astrocytes were exposed to 10 µM fluoxetine; 24 h post-treatment, a high-resolution proton nuclear magnetic resonance (1H NMR)-based metabolomic approach coupled with multivariate statistical analysis was used to characterize the metabolic variations of intracellular metabolites. The orthogonal partial least-squares discriminant analysis (OPLS-DA) score plots of the spectra demonstrated that the fluoxetine-treated astrocytes were significantly distinguished from the untreated controls. In total, 17 differential metabolites were identified to discriminate the two groups. These key metabolites were mainly involved in lipids, lipid metabolism-related molecules and amino acids. This is the ﬁrst study to indicate that fluoxetine may exert antidepressant action by regulating the astrocyte's lipid and amino acid metabolism. These findings should aid our understanding of the biological mechanisms underlying fluoxetine therapy.
Fluoxetine regulates neurogenesis in vitro through modulation of GSK-3β/β-catenin signaling.

PubMed

Hui, Jiaojie; Zhang, Jianping; Kim, Hoon; Tong, Chang; Ying, Qilong; Li, Zaiwang; Mao, Xuqiang; Shi, Guofeng; Yan, Jie; Zhang, Zhijun; Xi, Guangjun

2014-12-07

It is generally accepted that chronic treatment with antidepressants increases hippocampal neurogenesis, but the molecular mechanisms underlying their effects are unknown. Recently, glycogen synthase kinase-3 beta (GSK-3β)/β-catenin signaling was shown to be involved in the mechanism of how antidepressants might influence hippocampal neurogenesis. The aim of this study was to determine whether GSK-3β/β-catenin signaling is involved in the alteration of neurogenesis as a result of treatment with fluoxetine, a selective serotonin reuptake inhibitor. The mechanisms involved in fluoxetine's regulation of GSK-3β/β-catenin signaling pathway were also examined. Our results demonstrated that fluoxetine increased the proliferation of embryonic neural precursor cells (NPCs) by up-regulating the phosphorylation of Ser9 on GSK-3β and increasing the level of nuclear β-catenin. The overexpression of a stabilized β-catenin protein (ΔN89 β-catenin) significantly increased NPC proliferation, while inhibition of β-catenin expression in NPCs led to a significant decrease in the proliferation and reduced the proliferative effects induced by fluoxetine. The effects of fluoxetine-induced up-regulation of both phosphorylation of Ser9 on GSK-3β and nuclear β-catenin were significantly prevented by the 5-hydroxytryptamine-1A (5-HT1A) receptor antagonist WAY-100635. The results demonstrate that fluoxetine may increase neurogenesis via the GSK-3β/β-catenin signaling pathway that links postsynaptic 5-HT1A receptor activation. © The Author 2015. Published by Oxford University Press on behalf of CINP.
Effects of Fluoxetine on Hippocampal Neurogenesis and Neuroprotection in the Model of Global Cerebral Ischemia in Rats

PubMed Central

Kisel, Alena; Kudabaeva, Marina; Chernysheva, Galina; Smolyakova, Vera; Krutenkova, Elena; Wasserlauf, Irina; Plotnikov, Mark; Yarnykh, Vasily

2018-01-01

A selective serotonin reuptake inhibitor, fluoxetine, has recently attracted a significant interest as a neuroprotective therapeutic agent. There is substantial evidence of improved neurogenesis under fluoxetine treatment of brain ischemia in animal stroke models. We studied long-term effects of fluoxetine treatment on hippocampal neurogenesis, neuronal loss, inflammation, and functional recovery in a new model of global cerebral ischemia (GCI). Brain ischemia was induced in adult Wistar male rats by transient occlusion of three main vessels originating from the aortic arch and providing brain blood supply. Fluoxetine was injected intraperitoneally in a dose of 20 mg/kg for 10 days after surgery. To evaluate hippocampal neurogenesis at time points 10 and 30 days, 5-Bromo-2′-deoxyuridine was injected at days 8–10 after GCI. According to our results, 10-day fluoxetine injections decreased neuronal loss and inflammation, improved survival and functional recovery of animals, enhanced neurogenesis, and prevented an early pathological increase in neural stem cell recruitment in the subgranular zone (SGZ) of the hippocampus without reducing the number of mature neurons at day 30 after GCI. In summary, this study suggests that fluoxetine may provide a promising therapy in cerebral ischemia due to its neuroprotective, anti-inflammatory, and neurorestorative effect. PMID:29304004
Degradation and acute toxicity removal of the antidepressant Fluoxetine (Prozac(®)) in aqueous systems by electron beam irradiation.

PubMed

Silva, Vanessa Honda Ogihara; Dos Santos Batista, Ana Paula; Silva Costa Teixeira, Antonio Carlos; Borrely, Sueli Ivone

2016-06-01

Electron beam irradiation (EBI) has been considered an advanced technology for the treatment of water and wastewater, whereas very few previous investigations reported its use for removing pharmaceutical pollutants. In this study, the degradation of fluoxetine (FLX), an antidepressant marketed as Prozac(®), was investigated by using EBI at FLX initial concentration of 19.4 ± 0.2 mg L(-1). More than 90 % FLX degradation was achieved at 0.5 kGy, with FLX below the detection limit (0.012 mg L(-1)) at doses higher than 2.5 kGy. The elucidation of organic byproducts performed using direct injection mass spectrometry, along with the results of ion chromatography, indicated hydroxylation of FLX molecules with release of fluoride and nitrate anions. Nevertheless, about 80 % of the total organic carbon concentration remained even for 7.5 kGy or higher doses. The decreases in acute toxicity achieved 86.8 and 9.6 % for Daphnia similis and Vibrio fischeri after EBI exposure at 5 kGy, respectively. These results suggest that EBI could be an alternative to eliminate FLX and to decrease residual toxicity from wastewater generated in pharmaceutical formulation facilities, although further investigation is needed for correlating the FLX degradation mechanism with the toxicity results.
Evaluation of interleukin-6 and serotonin as biomarkers to predict response to fluoxetine.

PubMed

Manoharan, Aarthi; Rajkumar, Ravi Philip; Shewade, Deepak Gopal; Sundaram, Rajan; Muthuramalingam, Avin; Paul, Abialbon

2016-05-01

Only 30% of major depressive disorder (MDD) patients achieve complete remission with a serotonergic antidepressant (selective serotonin reuptake inhibitor). We investigated the potential of serotonin (5-HT) and interleukin-6 (IL-6) to serve as functional biomarkers of fluoxetine response. Serum IL-6 and 5-HT were measured in 73 MDD patients (39 responders and 34 non-responders) pre- and 6 weeks post-treatment and in 44 normal controls with ELISA. Fluoxetine and norfluoxetine were measured using LC MS/MS. IL-6 levels were significantly higher in MDD patients when compared with controls (p < 0.01), and 5-HT levels were significantly lower in non-responders compared with controls (p = 0.0131). Pre- and post-treatment levels of both biomarkers individually and in combination did not significantly differ between responders and non-responders. Area under the receiver operating characteristics curve for the biomarkers was 0.5. Significant correlation was seen between the percentage change in IL-6 and percentage change in Hamilton Rating Scale for Depression score in responders. Fluoxetine and norfluoxetine concentrations were not significantly different in responders and non-responders, and there was no correlation between fluoxetine concentrations and percentage reduction in 5-HT from week 0 to 6. 5-HT and IL-6 may not serve as useful markers of response to fluoxetine because of inconsistent results across different studies. Copyright © 2016 John Wiley & Sons, Ltd. Copyright © 2016 John Wiley & Sons, Ltd.
Determination of fluoxetine in pharmaceutical and biological samples based on the silver nanoparticle enhanced fluorescence of fluoxetine-terbium complex.

PubMed

Lotfi, Ali; Manzoori, Jamshid L

2016-11-01

In this study, a simple and sensitive spectrofluorimetric method is presented for the determination of fluoxetine based on the enhancing effect of silver nanoparticles (AgNPs) on the terbium-fluoxetine fluorescence emission. The AgNPs were prepared by a simple reduction method and characterized by UV-Vis spectroscopy and transmission electron microscopy. It was indicated that these AgNPs have a remarkable amplifying effect on the terbium-sensitized fluorescence of fluoxetine. The effects of various parameters such as AgNP and Tb 3+ concentration and the pH of the media were investigated. Under obtained optimal conditions, the fluorescence intensity of the terbium-fluoxetine-AgNP system was enhanced linearly by increasing the concentration of fluoxetine in the range of 0.008 to 19 mg/L. The limit of detection (b + 3s) was 8.3 × 10 -4 mg/L. The interference effects of common species found in real samples were also studied. The method had good linearity, recovery, reproducibility and sensitivity, and was satisfactorily applied for the determination of fluoxetine in tablet formulations, human urine and plasma samples. Copyright © 2016 John Wiley & Sons, Ltd. Copyright © 2016 John Wiley & Sons, Ltd.
BEHAVIORAL EFFECTS OF FLUOXETINE IN AN ANIMAL MODEL OF ANXIETY/DEPRESSION ARE MEDIATED BY BOTH NEUROGENESIS-DEPENDENT AND INDEPENDENT MECHANISMS

PubMed Central

David, Denis J.; Samuels, Benjamin Adam; Rainer, Quentin; Wang, Jing-Wen; Marsteller, Douglas; Mendez, Indira; Drew, Michael; Craig, Douglas A.; Guiard, Bruno P.; Guilloux, Jean-Philippe; Artymyshyn, Roman P.; Gardier, Alain M; Gerald, Christophe; Antonijevic, Irina A.; Leonardo, E. David; Hen, René

2009-01-01

SUMMARY Understanding the physiopathology of affective disorders and their treatment relies on the availability of experimental models that accurately mimic aspects of the disease. Here we describe a mouse model of an anxiety/depressive-like state induced by chronic corticosterone treatment. Furthermore, chronic antidepressant treatment reversed the behavioral dysfunctions and the inhibition of hippocampal neurogenesis induced by corticosterone treatment. In corticosterone-treated mice where hippocampal neurogenesis is abolished by X-irradiation, the efficacy of fluoxetine is blocked in some but not all behavioral paradigms, suggesting both neurogenesis-dependent and independent mechanisms of antidepressant actions. Finally, we identified a number of candidate genes, the expression of which is decreased by chronic corticosterone and normalized by chronic fluoxetine treatment selectively in the hypothalamus. Importantly, mice deficient in one of these genes, β-arrestin 2, displayed a reduced response to fluoxetine in multiple tasks, suggesting that β-arrestin signaling is necessary for the antidepressant effects of fluoxetine. PMID:19477151
Fluoxetine up-regulates expression of cellular FLICE-inhibitory protein and inhibits LPS-induced apoptosis in hippocampus-derived neural stem cell

DOE Office of Scientific and Technical Information (OSTI.GOV)

Chiou, S.-H.; Chen, S.-J.; Peng, C-H.

2006-05-05

Fluoxetine is a widely used antidepressant compound which inhibits the reuptake of serotonin in the central nervous system. Recent studies have shown that fluoxetine can promote neurogenesis and improve the survival rate of neurons. However, whether fluoxetine modulates the proliferation or neuroprotection effects of neural stem cells (NSCs) needs to be elucidated. In this study, we demonstrated that 20 {mu}M fluoxetine can increase the cell proliferation of NSCs derived from the hippocampus of adult rats by MTT test. The up-regulated expression of Bcl-2, Bcl-xL and the cellular FLICE-inhibitory protein (c-FLIP) in fluoxetine-treated NSCs was detected by real-time RT-PCR. Our resultsmore » further showed that fluoxetine protects the lipopolysaccharide-induced apoptosis in NSCs, in part, by activating the expression of c-FLIP. Moreover, c-FLIP induction by fluoxetine requires the activation of the c-FLIP promoter region spanning nucleotides -414 to -133, including CREB and SP1 sites. This effect appeared to involve the phosphatidylinositol-3-kinase-dependent pathway. Furthermore, fluoxetine treatment significantly inhibited the induction of proinflammatory factor IL-1{beta}, IL-6, and TNF-{alpha} in the culture medium of LPS-treated NSCs (p < 0.01). The results of high performance liquid chromatography coupled to electrochemical detection further confirmed that fluoxentine increased the functional production of serotonin in NSCs. Together, these data demonstrate the specific activation of c-FLIP by fluoxetine and indicate the novel role of fluoxetine for neuroprotection in the treatment of depression.« less
Preliminary randomized double-blind placebo-controlled trial of tryptophan combined with fluoxetine to treat major depressive disorder: antidepressant and hypnotic effects.

PubMed Central

Levitan, R D; Shen, J H; Jindal, R; Driver, H S; Kennedy, S H; Shapiro, C M

2000-01-01

OBJECTIVE: Because the initial phase of treatment of depression with a selective serotonin reuptake inhibitor is often complicated by a delayed onset of action of the antidepressant or severe insomnia or both, we investigated whether tryptophan, an amino acid with both antidepressant-augmenting and hypnotic effects, would benefit patients with depression at the beginning of treatment with fluoxetine. DESIGN: Randomized, double-blind, placebo-controlled trial. PATIENTS: Thirty individuals with major depressive disorder. INTERVENTIONS: Treatment over 8 weeks with 20 mg of fluoxetine per day and either tryptophan (2 to 4 g per day) or placebo. OUTCOME MEASURES: Mood was assessed using the 29-item Hamilton Depression Rating Scale (HDRS-29) and the Beck Depression Inventory (BDI). Laboratory sleep studies were done at baseline and after 4 and 8 weeks of treatment using standard procedures. RESULTS: During the first week of treatment, there was a significantly greater decrease in HDRS-29 depression scores, and a similar trend in BDI scores, in the tryptophan/fluoxetine group than in the placebo/fluoxetine group. No significant differences were noted at later time points. With respect to sleep measures, there was a significant group-by-time interaction for slow-wave sleep at week 4. Further analysis revealed a significant decrease in slow-wave sleep after 4 weeks of treatment in the placebo/fluoxetine group, but not in the tryptophan/fluoxetine group. No cases of serotonin syndrome occurred, and the combination was well tolerated, although the 4 g per day dosage of tryptophan produced daytime drowsiness. CONCLUSIONS: Combining 20 mg of fluoxetine with 2 g of tryptophan daily at the outset of treatment for major depressive disorder appears to be a safe protocol that may have both a rapid antidepressant effect and a protective effect on slow-wave sleep. Further large-scale studies are needed to confirm these initial findings. PMID:11022398
Modulation of the subthalamic nucleus activity by serotonergic agents and fluoxetine administration.

PubMed

Aristieta, A; Morera-Herreras, T; Ruiz-Ortega, J A; Miguelez, C; Vidaurrazaga, I; Arrue, A; Zumarraga, M; Ugedo, L

2014-05-01

Within the basal ganglia, the subthalamic nucleus (STN) is the only glutamatergic structure and occupies a central position in the indirect pathway. In rat, the STN receives serotonergic input from the dorsal raphe nucleus and expresses serotonergic receptors. This study examined the consequences of serotonergic neurotransmission modulation on STN neuron activity. In vivo single-unit extracellular recordings, HPLC determination, and rotarod and bar test were performed in control, 4-chloro-DL-phenylalanine methyl ester hydrochloride- (pCPA, a serotonin synthesis inhibitor) and chronically fluoxetine-treated rats. The pCPA treatment and the administration of serotonin (5-HT) receptor antagonists increased number of bursting neurons in the STN. The systemic administration of the 5-HT(1A) agonist, 8-OH-DPAT, decreased the firing rate and increased the coefficient of variation of STN neurons in pCPA-treated rats but not in control animals. Additionally, microinjection of 8-OH-DPAT into the STN reduced the firing rate of STN neurons, while microinjection of the 5-HT(2C) agonist, Ro 60-0175, increased the firing rate in both control and fluoxetine-treated animals. Finally, the fluoxetine challenge increased the firing rate of STN neurons in fluoxetine-treated rats and induced catalepsy. Our results indicate that the depletion and the blockage of 5-HT modify STN neuron firing pattern. STN neuron activity is under the control of 5-HT(1A) and 5-HT(2C) receptors located both inside and outside the STN. Finally, fluoxetine increases STN neuron activity in chronically fluoxetine-treated rats, which may explain the role of this nucleus in fluoxetine-induced extrapyramidal side effects.
Corticosterone Facilitates Fluoxetine-Induced Neuronal Plasticity in the Hippocampus

PubMed Central

Kobayashi, Katsunori; Ikeda, Yumiko; Asada, Minoru; Inagaki, Hirofumi; Kawada, Tomoyuki; Suzuki, Hidenori

2013-01-01

The hippocampal dentate gyrus has been implicated in a neuronal basis of antidepressant action. We have recently shown a distinct form of neuronal plasticity induced by the serotonergic antidepressant fluoxetine, that is, a reversal of maturation of the dentate granule cells in adult mice. This “dematuration” is induced in a large population of dentate neurons and maintained for at least one month after withdrawal of fluoxetine, suggesting long-lasting strong influence of dematuration on brain functioning. However, reliable induction of dematuration required doses of fluoxetine higher than suggested optimal doses for mice (10 to 18 mg/kg/day), which casts doubt on the clinical relevance of this effect. Since our previous studies were performed in naive mice, in the present study, we reexamined effects of fluoxetine using mice treated with chronic corticosterone that model neuroendocrine pathophysiology associated with depression. In corticosterone-treated mice, fluoxetine at 10 mg/kg/day downregulated expression of mature granule cell markers and attenuated strong frequency facilitation at the synapse formed by the granule cell axon mossy fiber, suggesting the induction of granule cell dematuration. In addition, fluoxetine caused marked enhancement of dopaminergic modulation at the mossy fiber synapse. In vehicle-treated mice, however, fluoxetine at this dose had no significant effects. The plasma level of fluoxetine was comparable to that in patients taking chronic fluoxetine, and corticosterone did not affect it. These results indicate that corticosterone facilitates fluoxetine-induced plastic changes in the dentate granule cells. Our finding may provide insight into neuronal mechanisms underlying enhanced responsiveness to antidepressant medication in certain pathological conditions. PMID:23675498
Cytotoxicity and mutagenicity of fluoxetine hydrochloride (Prozac), with or without vitamins A and C, in plant and animal model systems.

PubMed

Düsman, E; Almeida, I V; Mariucci, R G; Mantovani, M S; Vicentini, V E P

2014-01-28

Fluoxetine, commonly known as Prozac, is the first representative of the so-called new generation of antidepressants that promise efficacy, with few side effects, against deep depression, nervous bulimia, and anxiety. As there is a growing number of people suffering from anxiety and depression; consequently, the use of fluoxetine is also increasing. Verifying absence of drug effects such as cytotoxicity or mutagenicity is of great importance. Certain vitamins, such as vitamin A (retinol, retinoids) and vitamin C (ascorbic acid) protect and are extremely active against mutagens. We evaluated the cytotoxic and mutagenic activity of fluoxetine, with and without concomitant administration of vitamin A or C, in Allium cepa meristem cells and Wistar rat bone marrow cells. The A. cepa meristem cells showed fluoxetine cytotoxicity; concomitant treatment with vitamin A or C proved non-protective. Treatment of Wistar rats with fluoxetine intraperitoneally or via gavage did not affect cell division or cause clastogenic effects. Vitamin A and C did not affect the cytotoxicity or mutagenicity of fluoxetine in the rat cells.
Differential Peripheral Proteomic Biosignature of Fluoxetine Response in a Mouse Model of Anxiety/Depression

PubMed Central

Mendez-David, Indira; Boursier, Céline; Domergue, Valérie; Colle, Romain; Falissard, Bruno; Corruble, Emmanuelle; Gardier, Alain M.; Guilloux, Jean-Philippe; David, Denis J.

2017-01-01

The incorporation of peripheral biomarkers in the treatment of major depressive disorders (MDD) could improve the efficiency of treatments and increase remission rate. Peripheral blood mononuclear cells (PBMCs) represent an attractive biological substrate allowing the identification of a drug response signature. Using a proteomic approach with high-resolution mass spectrometry, the present study aimed to identify a biosignature of antidepressant response (fluoxetine, a Selective Serotonin Reuptake Inhibitor) in PBMCs in a mouse model of anxiety/depression. Following determination of an emotionality score, using complementary behavioral analysis of anxiety/depression across three different tests (Elevated Plus Maze, Novelty Suppressed Feeding, Splash Test), we showed that a 4-week corticosterone treatment (35 μg/ml, CORT model) in C57BL/6NTac male mice induced an anxiety/depressive-like behavior. Then, chronic fluoxetine treatment (18 mg/kg/day for 28 days in the drinking water) reduced corticosterone-induced increase in emotional behavior. However, among 46 fluoxetine-treated mice, only 30 of them presented a 50% decrease in emotionality score, defining fluoxetine responders (CORT/Flx-R). To determine a peripheral biological signature of fluoxetine response, proteomic analysis was performed from PBMCs isolated from the “most” affected corticosterone/vehicle (CORT/V), corticosterone/fluoxetine responders and non-responders (CORT/Flx-NR) animals. In comparison to CORT/V, a total of 263 proteins were differently expressed after fluoxetine exposure. Expression profile of these proteins showed a strong similarity between CORT/Flx-R and CORT/Flx-NR (R = 0.827, p < 1e-7). Direct comparison of CORT/Flx-R and CORT/Flx-NR groups revealed 100 differently expressed proteins, representing a combination of markers associated either with the maintenance of animals in a refractory state, or associated with behavioral improvement. Finally, 19 proteins showed a differential
Direct inhibition of retinoic acid catabolism by fluoxetine.

PubMed

Hellmann-Regen, Julian; Uhlemann, Ria; Regen, Francesca; Heuser, Isabella; Otte, Christian; Endres, Matthias; Gertz, Karen; Kronenberg, Golo

2015-09-01

Recent evidence from animal and human studies suggests neuroprotective effects of the SSRI fluoxetine, e.g., in the aftermath of stroke. The underlying molecular mechanisms remain to be fully defined. Because of its effects on the cytochrome P450 system (CYP450), we hypothesized that neuroprotection by fluoxetine is related to altered metabolism of retinoic acid (RA), whose CYP450-mediated degradation in brain tissue constitutes an important step in the regulation of its site-specific auto- and paracrine actions. Using traditional pharmacological in vitro assays, the effects of fluoxetine on RA degradation were probed in crude synaptosomes from rat brain and human-derived SH-SY5Y cells, and in cultures of neuron-like SH-SY5Y cells. Furthermore, retinoid-dependent effects of fluoxetine on neuronal survival following glutamate exposure were investigated in rat primary neurons cells using specific retinoid receptor antagonists. Experiments revealed dose-dependent inhibition of synaptosomal RA degradation by fluoxetine along with dose-dependent increases in RA levels in cell cultures. Furthermore, fluoxetine's neuroprotective effects against glutamate excitotoxicity in rat primary neurons were demonstrated to partially depend on RA signaling. Taken together, these findings demonstrate for the first time that the potent, pleiotropic antidepressant fluoxetine directly interacts with RA homeostasis in brain tissue, thereby exerting its neuroprotective effects.
1H NMR-Based Metabolic Profiling Reveals the Effects of Fluoxetine on Lipid and Amino Acid Metabolism in Astrocytes

PubMed Central

Bai, Shunjie; Zhou, Chanjuan; Cheng, Pengfei; Fu, Yuying; Fang, Liang; Huang, Wen; Yu, Jia; Shao, Weihua; Wang, Xinfa; Liu, Meiling; Zhou, Jingjing; Xie, Peng

2015-01-01

Fluoxetine, a selective serotonin reuptake inhibitor (SSRI), is a prescribed and effective antidepressant and generally used for the treatment of depression. Previous studies have revealed that the antidepressant mechanism of fluoxetine was related to astrocytes. However, the therapeutic mechanism underlying its mode of action in astrocytes remains largely unclear. In this study, primary astrocytes were exposed to 10 µM fluoxetine; 24 h post-treatment, a high-resolution proton nuclear magnetic resonance (1H NMR)-based metabolomic approach coupled with multivariate statistical analysis was used to characterize the metabolic variations of intracellular metabolites. The orthogonal partial least-squares discriminant analysis (OPLS-DA) score plots of the spectra demonstrated that the fluoxetine-treated astrocytes were significantly distinguished from the untreated controls. In total, 17 differential metabolites were identified to discriminate the two groups. These key metabolites were mainly involved in lipids, lipid metabolism-related molecules and amino acids. This is the first study to indicate that fluoxetine may exert antidepressant action by regulating the astrocyte’s lipid and amino acid metabolism. These findings should aid our understanding of the biological mechanisms underlying fluoxetine therapy. PMID:25884334
Effects of Fluoxetine and Visual Experience on Glutamatergic and GABAergic Synaptic Proteins in Adult Rat Visual Cortex123

PubMed Central

Beshara, Simon; Beston, Brett R.; Pinto, Joshua G. A.

2015-01-01

Abstract Fluoxetine has emerged as a novel treatment for persistent amblyopia because in adult animals it reinstates critical period-like ocular dominance plasticity and promotes recovery of visual acuity. Translation of these results from animal models to the clinic, however, has been challenging because of the lack of understanding of how this selective serotonin reuptake inhibitor affects glutamatergic and GABAergic synaptic mechanisms that are essential for experience-dependent plasticity. An appealing hypothesis is that fluoxetine recreates a critical period (CP)-like state by shifting synaptic mechanisms to be more juvenile. To test this we studied the effect of fluoxetine treatment in adult rats, alone or in combination with visual deprivation [monocular deprivation (MD)], on a set of highly conserved presynaptic and postsynaptic proteins (synapsin, synaptophysin, VGLUT1, VGAT, PSD-95, gephyrin, GluN1, GluA2, GluN2B, GluN2A, GABAAα1, GABAAα3). We did not find evidence that fluoxetine shifted the protein amounts or balances to a CP-like state. Instead, it drove the balances in favor of the more mature subunits (GluN2A, GABAAα1). In addition, when fluoxetine was paired with MD it created a neuroprotective-like environment by normalizing the glutamatergic gain found in adult MDs. Together, our results suggest that fluoxetine treatment creates a novel synaptic environment dominated by GluN2A- and GABAAα1-dependent plasticity. PMID:26730408
Fluoxetine elevates allopregnanolone in female rat brain but inhibits a steroid microsomal dehydrogenase rather than activating an aldo-keto reductase

PubMed Central

Fry, J P; Li, K Y; Devall, A J; Cockcroft, S; Honour, J W; Lovick, T A

2014-01-01

Background and Purpose Fluoxetine, a selective serotonin reuptake inhibitor, elevates brain concentrations of the neuroactive progesterone metabolite allopregnanolone, an effect suggested to underlie its use in the treatment of premenstrual dysphoria. One report showed fluoxetine to activate the aldo-keto reductase (AKR) component of 3α-hydroxysteroid dehydrogenase (3α-HSD), which catalyses production of allopregnanolone from 5α-dihydroprogesterone. However, this action was not observed by others. The present study sought to clarify the site of action for fluoxetine in elevating brain allopregnanolone. Experimental Approach Adult male rats and female rats in dioestrus were treated with fluoxetine and their brains assayed for allopregnanolone and its precursors, progesterone and 5α-dihydroprogesterone. Subcellular fractions of rat brain were also used to investigate the actions of fluoxetine on 3α-HSD activity in both the reductive direction, producing allopregnanolone from 5α-dihydroprogesterone, and the reverse oxidative direction. Fluoxetine was also tested on these recombinant enzyme activities expressed in HEK cells. Key Results Short-term treatment with fluoxetine increased brain allopregnanolone concentrations in female, but not male, rats. Enzyme assays on native rat brain fractions and on activities expressed in HEK cells showed fluoxetine did not affect the AKR producing allopregnanolone from 5α-dihydroprogesterone but did inhibit the microsomal dehydrogenase oxidizing allopregnanolone to 5α-dihydroprogesterone. Conclusions and Implications Fluoxetine elevated allopregnanolone in female rat brain by inhibiting its oxidation to 5α-dihydroprogesterone by a microsomal dehydrogenase. This is a novel site of action for fluoxetine, with implications for the development of new agents and/or dosing regimens to raise brain allopregnanolone. PMID:25161074

The psychoactive pollutant fluoxetine compromises antipredator behaviour in fish.

PubMed

Martin, Jake M; Saaristo, Minna; Bertram, Michael G; Lewis, Phoebe J; Coggan, Timothy L; Clarke, Bradley O; Wong, Bob B M

2017-03-01

Pharmaceuticals are increasingly being detected in aquatic ecosystems worldwide. Particularly concerning are pharmaceutical pollutants that can adversely impact exposed wildlife, even at extremely low concentrations. One such contaminant is the widely prescribed antidepressant fluoxetine, which can disrupt neurotransmission and behavioural pathways in wildlife. Despite this, relatively limited research has addressed the behavioural impacts of fluoxetine at ecologically realistic exposure concentrations. Here, we show that 28-day fluoxetine exposure at two ecologically relevant dosages-one representing low surface water concentrations and another representing high effluent flow concentrations-alters antipredator behaviour in Eastern mosquitofish (Gambusia holbrooki). We found that fluoxetine exposure at the lower dosage resulted in increased activity levels irrespective of the presence or absence of a predatory dragonfly nymph (Hemianax papuensis). Additionally, irrespective of exposure concentration, fluoxetine-exposed fish entered the predator 'strike zone' more rapidly. In a separate experiment, fluoxetine exposure reduced mosquitofish freezing behaviour-a common antipredator strategy-following a simulated predator strike, although, in females, this reduction in behaviour was seen only at the lower dosage. Together, our findings suggest that fluoxetine can cause both non-monotonic and sex-dependent shifts in behaviour. Further, they demonstrate that exposure to fluoxetine at environmentally realistic concentrations can alter antipredator behaviour, with important repercussions for organismal fitness. Copyright © 2016 Elsevier Ltd. All rights reserved.
Comparing effects of citalopram with fluoxetine on sleep quality in patients with major depressive disorder.

PubMed

Shahsavand-Ananloo, E; Berenji, F; Sadeghniiat, K; Alimadadi, A; Zahiroddin, A R; Tabatabaee, M; Abbasi-Asl, M; Ghaeli, P

2013-05-01

Sleep disturbance is a common complaint in major depressive disorder (MDD) including impairment of both subjective and objective parameters. All antidepressants affect sleep architecture and quality. This trial was designed to compare the effects of short-term use of citalopram with fluoxetine on sleep quality (SQ) of patients with MDD based on Diagnostic and Statistical Manual for Mental Disorders - Text Revision 4th edition (DSM-IV-TR) criteria. Patients who met the study criteria entered this open-label study. Sleep quality and depression severity were evaluated by using Pittsburgh Sleep Quality Index (PSQI) and Beck Depression Inventory-II (BDI-II), respectively. Patients could not have received any antidepressant for at least one month prior entering the study. Subjects were assigned to receive either fluoxetine or citalopram for 8 weeks. The relationships between SQ and severity of depression were also studied at weeks 4 and 8. Data was analyzed by using SPSS 11.5 version. Nineteen patients received fluoxetine 20-40 mg/day and 21 received citalopram 20-40 mg/day. After 4 and 8 weeks treatment with both fluoxetine and citalopram, significant improvements in SQ were noted in both groups. However, no significant difference between the two groups was observed. Additionally, a significant and positive correlation between improvements in SQ and depression was noted after 8 weeks treatment with citalopram but not with fluoxetine. This study noted that both citalopram and fluoxetine improved SQ in outpatients with MDD after 8 weeks without any significant difference between the 2 groups.
Antidepressant-like effects of the xanthine oxidase enzyme inhibitor allopurinol in rats. A comparison with fluoxetine.

PubMed

Gürbüz Özgür, Börte; Aksu, Hatice; Birincioğlu, Mustafa; Dost, Turhan

2015-11-01

Allopurinol is a xanthine oxidase enzyme inhibitor that is widely used for the treatment of hyperuricemia and gout. The activity of tryptophan 2,3-dioxygenase, which metabolizes tryptophan (TRP), is decreased by xanthine oxidase inhibitors, causing TRP levels in the body to be increased. Increases in TRP levels in the brain might have antidepressant effects. The purpose of this study is to evaluate the antidepressant effects of allopurinol compared to those of fluoxetine, which is a proven antidepressant. Thirty-two Wistar albino male rats were divided into four groups (control, 10mg/kg fluoxetine, 50mg/kg allopurinol, 50mg/kg allopurinol+10 mg/kg fluoxetine; n=8 per group), and forced swimming tests were performed before and after 14days of drug administration. Serotonin, 5-hydroxyindolacetic acid and uric acid levels were measured in blood samples after the final treatment. When allopurinol and fluoxetine were administered separately, a decrease in the duration of immobility and an increased duration of swimming were observed in the forced swimming test. The results showed similar antidepressant efficacies between allopurinol and fluoxetine. However, we found no statistically significant difference in the antidepressant effect of the combined therapy versus single drug therapy. Copyright © 2015 Elsevier Inc. All rights reserved.
Fluoxetine Regulates Neurogenesis In Vitro Through Modulation of GSK-3β/β-Catenin Signaling

PubMed Central

Hui, Jiaojie; Zhang, Jianping; Kim, Hoon; Tong, Chang; Ying, Qilong; Li, Zaiwang; Mao, Xuqiang; Shi, Guofeng; Yan, Jie; Zhang, Zhijun

2015-01-01

Background: It is generally accepted that chronic treatment with antidepressants increases hippocampal neurogenesis, but the molecular mechanisms underlying their effects are unknown. Recently, glycogen synthase kinase-3 beta (GSK-3β)/β-catenin signaling was shown to be involved in the mechanism of how antidepressants might influence hippocampal neurogenesis. Methods: The aim of this study was to determine whether GSK-3β/β-catenin signaling is involved in the alteration of neurogenesis as a result of treatment with fluoxetine, a selective serotonin reuptake inhibitor. The mechanisms involved in fluoxetine’s regulation of GSK-3β/β-catenin signaling pathway were also examined. Results: Our results demonstrated that fluoxetine increased the proliferation of embryonic neural precursor cells (NPCs) by up-regulating the phosphorylation of Ser9 on GSK-3β and increasing the level of nuclear β-catenin. The overexpression of a stabilized β-catenin protein (ΔN89 β-catenin) significantly increased NPC proliferation, while inhibition of β-catenin expression in NPCs led to a significant decrease in the proliferation and reduced the proliferative effects induced by fluoxetine. The effects of fluoxetine-induced up-regulation of both phosphorylation of Ser9 on GSK-3β and nuclear β-catenin were significantly prevented by the 5-hydroxytryptamine-1A (5-HT1A) receptor antagonist WAY-100635. Conclusions: The results demonstrate that fluoxetine may increase neurogenesis via the GSK-3β/β-catenin signaling pathway that links postsynaptic 5-HT1A receptor activation. PMID:25522429
The Distribution of Fluoxetine and Norfluoxetine in Postmortem Fluids and Tissues

DTIC Science & Technology

2007-06-01

of fluoxetine and nor- fluoxetine in dogs following oral administration of fluoxetine hydrochloride ( Prozac ). J Forensic Sci, 42(5):812-6, 1997. 6...flight crews are submitted to the Federal Aviation Administration’s Civil Aerospace Medical Institute for toxicological analysis. Fluoxetine ( Prozac ...heart muscle, and brain. Specimens were extracted using solid-phase extraction and analyzed by GC/MS. Deuterated fluoxetine and norfluoxetine were
Chronic administration of fluoxetine and pro-inflammatory cytokine change in a rat model of depression.

PubMed

Lu, Yanxia; Ho, Cyrus S; Liu, Xin; Chua, Anna N; Wang, Wei; McIntyre, Roger S; Ho, Roger C

2017-01-01

This study evaluated the chronic effects of fluoxetine, a commonly prescribed SSRI antidepressant, on the peripheral and central levels of inflammatory cytokines including IL-1β, IL-6, TNF-α and IL-17 over a 4-interval in a rat model of chronic mild stress (CMS) which resembles the human experience of depression. Twenty-four Sprague-Dawley rats were randomly assigned to CMS+vehicle (n = 9), CMS+fluoxetine (n = 9) and the control (n = 6) groups. Sucrose preference and forced swim tests were performed to assess behavioral change. Blood samples were collected on day 0, 60, 90 and 120 for measurement of cytokine levels in plasma. On day 120, the brain was harvested and central level of cytokines was tested using Luminex. Four months of fluoxetine treatment resulted in changes in the sucrose preference and immobility time measurements, commensurate with antidepressant effects. The CMS+vehicle group exhibited elevated plasma levels of IL-1β, IL-17, and TNF-α on day 60 or 120. Rats treated with fluoxetine demonstrated lower IL-1β in plasma and brain after 90 and 120-day treatment respectively (p<0.05). There was a trend of reduction of IL-6 and TNF-α concentration. This study revealed the potential therapeutic effects of fluoxetine by reducing central and peripheral levels of IL-1β in the alleviation of depressive symptoms.
Drug-nutrient interactions: inhibition of amino acid intestinal absorption by fluoxetine.

PubMed

Urdaneta, E; Idoate, I; Larralde, J

1998-05-01

Fluoxetine is one of the most widely used antidepressants and nowadays it is also being used to manage obesity problems. In our laboratory we demonstrated that the drug inhibited sugar absorption (Monteiro et al. 1993). The aim of the present work was to determine the effect of fluoxetine on intestinal leucine absorption. Using a procedure of successive absorptions in vivo the drug diminished amino acid absorption by 30% (P < 0.001). Experiments in vitro in isolated jejunum also revealed a reduction in leucine uptake of 37% (P < 0.001). In both cases fluoxetine only affected mediated transport without altering diffusion. In a preparation enriched in basolateral membrane, fluoxetine inhibited the Na+,K(+)-ATPase (EC 3.6.1.37) activity (55%; P < 0.001) in a non-competitive manner with an inhibition constant (Ki) value of 0.92 mM. Leucine uptake by brush-border membrane vesicles was diminished by the drug (a reduction of 48% was observed at 30s, P < 0.001); only the apical Na(+)-dependent transport system of the amino acid was modified and the inhibition was non-competitive. Leucine uptake in the presence of lysine indicated that transporter B was involved. These results suggest that fluoxetine reduces leucine absorption by its action on the basolateral and apical membrane of the enterocyte; the nutritional status of the patients under drug treatment may be affected as neutral amino acid absorption is decreased.
Anti-inflammatory and ameliorative effects of gallic acid on fluoxetine-induced oxidative stress and liver damage in rats.

PubMed

Karimi-Khouzani, Omid; Heidarian, Esfandiar; Amini, Sayed Asadollah

2017-08-01

Fluoxetine-induced liver damage is a cause of chronic liver disease. In the present study the hepatoprotective effects of gallic acid against fluoxetine-induced liver damage were examined. Forty-eight male rats were divided into six groups as follow: group 1, the control group; group 2, rats receiving fluoxetine (24mg/kg bw daily, po) without treatment; group 3, rats receiving 24mg/kg bw fluoxetine, treated with 50mg/kg bw silymarin and groups 4, 5, and 6 in which gallic acid (50, 100, and 200mg/kg bw, po, respectively) was prescribed after the consumption of fluoxetine. The histopathological changes of hepatic tissues were checked out. Fluoxetine caused a significant increase in the levels of serum glutamate oxaloacetate transaminase (GOT), serum glutamate pyruvate transaminase (GPT), lipid profiles, urea, fasting blood sugar (FBS), creatinine (Cr), protein carbonyl (PC) content, malondialdehyde (MDA), and liver TNF-α as an inflammatory element. Also, the obtained results of group 2 revealed a significant decline in ferric reducing ability of plasma (FRAP), liver catalase (CAT), superoxide dismutase (SOD), and vitamin C levels. The treatment with gallic acid showed significant ameliorations in abnormalities of fluoxetine-induced liver injury as represented by the improvement of hepatic CAT, SOD activities, vitamin C levels, serum biochemical parameters, and histopathological changes, in addition to the recovery of antioxidant defense system status. Gallic acid has inhibitory effects on fluoxetine-induced liver damage. The effect of gallic acid is derived from free radical scavenging properties and the anti-inflammatory effect related to TNF-α. Copyright © 2017. Published by Elsevier Urban & Partner Sp. z o.o.
Comparing omeprazole with fluoxetine for treatment of patients with heartburn and normal endoscopy who failed once daily proton pump inhibitors: double-blind placebo-controlled trial.

PubMed

Ostovaneh, M R; Saeidi, B; Hajifathalian, K; Farrokhi-Khajeh-Pasha, Y; Fotouhi, A; Mirbagheri, S S; Emami, H; Barzin, G; Mirbagheri, S A

2014-05-01

Patients with heartburn but without esophageal erosion respond less well to proton pump inhibitors (PPIs). There is a growing body of evidence implicating the role of psychological comorbidities in producing reflux symptoms. Pain modulators improve symptoms in patients with other functional gastrointestinal disorders. We aimed to compare the efficacy of fluoxetine with omeprazole and placebo to achieve symptomatic relief in patients with heartburn and normal endoscopy who failed once daily PPIs. Endoscopy-negative patients with heartburn who failed once daily PPIs were randomly allocated to receive 6 weeks treatment of fluoxetine, omeprazole, or placebo. Random allocation was stratified according to ambulatory pH monitoring study. Percentage of heartburn-free days and symptom severity was assessed. Sixty patients with abnormal and 84 patients with normal pH test were randomized. Subjects receiving fluoxetine experienced more improvement in percentage of heartburn-free days (median 35.7, IQR 21.4-57.1) than those on omeprazole (median 7.14, IQR 0-50, p < 0.001) or placebo (median 7.14, IQR 0-33.6, p < 0.001). In normal pH subgroup, fluoxetine was superior to both omeprazole and placebo regarding percentage of heartburn-free days (median improvement, 57.1, IQR 35.7-57.1 vs 13.9, IQR, 0-45.6 and 7.14, 0-23.8, respectively, p < 0.001), but no significant difference was observed between medications in abnormal pH subgroup. Fluoxetine was superior to omeprazole for improving the symptoms of patients with heartburn and normal endoscopy who failed once daily PPIs. The superiority of fluoxetine was mostly attributed to those with normal esophageal pH rather than those with abnormal pH (ClinicalTrials.gov, number NCT01269788). © 2014 John Wiley & Sons Ltd.
The Treatment for Adolescents with Depression Study (TADS): Demographic and Clinical Characteristics

ERIC Educational Resources Information Center

n/a; n/a

2005-01-01

Objective: The Treatment for Adolescents With Depression Study is a multicenter, randomized clinical trial sponsored by the NIMH. This study is designed to evaluate the short- and long-term effectiveness of four treatments for adolescents with major depressive disorder: fluoxetine, cognitive-behavioral therapy, their combination, and, acutely,…
Comparison of fluoxetine and 1-methyl-L-tryptophan in treatment of depression-like illness in Bacillus Calmette-Guerin-induced inflammatory model of depression in mice.

PubMed

Rana, Proteesh; Sharma, Amit K; Jain, Smita; Deshmukh, Pravin; Bhattacharya, S K; Banerjee, B D; Mediratta, Pramod K

2016-11-01

The inflammatory response system has been implicated in the pathophysiology of major depression. The pro-inflammatory cytokines like interferon-γ induce the enzyme indoleamine-2,3-dioxygenase (IDO) of the kynurenine pathway of tryptophan metabolism. The induction of IDO reduces the availability of tryptophan for serotonin synthesis. Furthermore, the metabolites of kynurenine pathway have neurotoxic property, which along with decreased serotonin may account for depression-like illness. The aim of this study was to compare the effects of treatment with fluoxetine and 1-methyl-L-tryptophan (1-MT) on Bacillus Calmette-Guerin (BCG)-induced inflammatory model of depression in mice. Behavioral tests included locomotor activity, forced swim test (FST) and tail suspension test (TST). Oxidative stress was assessed by examining the levels of thiobarbituric acid reactive species (TBARS) and non-protein thiols (NP-SH) in homogenized whole brain samples. Comet assays were performed to assess neurotoxicity. The results of this study demonstrate that BCG treatment resulted in an increase in duration of immobility in FST and TST as compared to the saline group. Further, it produced a significant increase in the brain TBARS levels and decrease in the brain NP-SH levels. The hippocampal tissue from BCG group had significantly more comet cells than the saline group. 1-MT and fluoxetine were able to reverse the BCG-induced depression-like behavior and the derangement in oxidative stress parameters. Fluoxetine and 1-MT also reversed the BCG-induced neurotoxicity in such mice. 1-Methyl-L-tryptophan exhibits antidepressant-like effect comparable to that of fluoxetine in treating BCG-induced depression-like behavior in mice.
An exploratory study of adolescent response to fluoxetine using psychological and biological predictors.

PubMed

Zohar, Ada H; Eilat, Tamar; Amitai, Maya; Taler, Michal; Bari, Romi; Chen, Alon; Apter, Alan; Weizman, Avraham; Fennig, Silvana

2018-01-01

Not enough is known about predicting therapeutic response to serotonin-specific reuptake inhibitors, and specifically to fluoxetine. This exploratory study used psychological and biological markers for (retrospective) prediction of treatment-response to fluoxetine in depressed and/or anxious adolescents. Forty-one consecutive adolescent outpatients with a primary diagnosis of severe affective and/or anxiety disorders were assessed and treated with an open-label 8-week trial of fluoxetine. Type D personality was assessed with the 14-item questionnaire, the DS14. In addition, TNFα, IL-6, and IL-1b were measured pre- and post-treatment. There was an elevation of Type D personality in patients, compared to the adolescent population rate. Post-treatment, 44% of patients were classified as non-responders; the relative risk of non-response for Type D personality patients was 2.8. Binary logistic regression predicting response vs. non-response showed a contribution of initial TNFα levels as well as Type D personality to non-response. In this exploratory study, the most significant contributor to non-response was Type D personality. However, the measurement of Type D was not prospective, and thus may be confounded with psychiatric morbidity. The measurement of personality in psychiatric settings may contribute to the understanding of treatment response and have clinical utility.
Acute and constitutive increases in central serotonin levels reduce social play behaviour in peri-adolescent rats

PubMed Central

Schiepers, Olga J. G.; Schoffelmeer, Anton N. M.; Cuppen, Edwin; Vanderschuren, Louk J. M. J.

2007-01-01

Rationale Serotonin is an important modulator of social behaviour. Individual differences in serotonergic signalling are considered to be a marker of personality that is stable throughout lifetime. While a large body of evidence indicates that central serotonin levels are inversely related to aggression and sexual behaviour in adult rats, the relationship between serotonin and social behaviour during peri-adolescence has hardly been explored. Objective To study the effect of acute and constitutive increases in serotonin neurotransmission on social behaviour in peri-adolescent rats. Materials and methods Social behaviour in peri-adolesent rats (28–35 days old) was studied after genetic ablation of the serotonin transporter, causing constitutively increased extra-neuronal serotonin levels, and after acute treatment with the serotonin reuptake inhibitor fluoxetine or the serotonin releasing agent 3,4-methylenedioxymethamphetamine (MDMA). A distinction was made between social play behaviour that mainly occurs during peri-adolescence, and non-playful social interactions that are abundant during the entire lifespan of rats. Results In serotonin transporter knockout rats, social play behaviour was markedly reduced, while non-playful aspects of social interaction were unaffected. Acute treatment with fluoxetine or MDMA dose-dependently inhibited social play behaviour. MDMA also suppressed non-playful social interaction but at higher doses than those required to reduce social play. Fluoxetine did not affect non-playful social interaction. Conclusions These data show that both acute and constitutive increases in serotonergic neurotransmission reduce social play behaviour in peri-adolescent rats. Together with our previous findings of reduced aggressive and sexual behaviour in adult serotonin transporter knockout rats, these data support the notion that serotonin modulates social behaviour in a trait-like manner. PMID:17661017
Effect of Fluoxetine on the Hippocampus of Wistar Albino Rats in Cold Restraint Stress Model

PubMed Central

Raghunath, Gunapriya; Ilango, Saraswathi; Vijayakumar, J; Vijayaraghavan, R

2017-01-01

Introduction Stress has been known to be a potential modulator of learning and memory. Long term stress can lead to depression. Fluoxetine is a selective serotonin reuptake inhibitor group of drug used in the treatment of depression. Aim The present study was conducted to evaluate the potential of Fluoxetine on cold restraint induced stress in the hippocampus of Wistar rats. Materials and Methods A total of 18 male wistar albino rats were divided randomly into three groups (n=6). Group 1 was the control group which were kept in normal laboratory conditions. Group 2 was the negative control group which were given cold restraint stress for period of four weeks. Group 3 was the experimental group, where the animals were pretreated with fluoxetine 10 mg/kg for a period of one week followed by cold restraint stress for 30 minutes and cotreated with fluoxetine 10 mg/kg for a period of four weeks. The whole study was done for a period of five weeks followed by behavioural studies and subsequently sacrificed with removal of brain for various histological, Immunohistochemical (IHC), neurochemical and antioxidant analysis. The values were expressed as Mean±SEM. One-way analysis of variance followed by Tukey’s multiple comparisons test was used for the comparison of means. A probability of 0.05 and less was taken as statistically significant using Prism Graphpad software version 6.01. Results The results show there was significant improvement in the Morris water maze test after treatment with fluoxetine in Group 2. Similar results were also noted in the levels of neurotransmitters and antioxidant levels in brain and also in the number of cells counted in IHC and histological studies by H&E when Group 3 was compared with Group 2. The treatment reversed the damage in Group 2 which was comparable with the control group. Conclusion The results revealed that administration of fluoxetine 10 mg/kg given orally has a potential antistressor effect by improving the neurogenic and
Effect of Fluoxetine on the Hippocampus of Wistar Albino Rats in Cold Restraint Stress Model.

PubMed

Jayakumar, Saikarthik; Raghunath, Gunapriya; Ilango, Saraswathi; Vijayakumar, J; Vijayaraghavan, R

2017-06-01

Stress has been known to be a potential modulator of learning and memory. Long term stress can lead to depression. Fluoxetine is a selective serotonin reuptake inhibitor group of drug used in the treatment of depression. The present study was conducted to evaluate the potential of Fluoxetine on cold restraint induced stress in the hippocampus of Wistar rats. A total of 18 male wistar albino rats were divided randomly into three groups (n=6). Group 1 was the control group which were kept in normal laboratory conditions. Group 2 was the negative control group which were given cold restraint stress for period of four weeks. Group 3 was the experimental group, where the animals were pretreated with fluoxetine 10 mg/kg for a period of one week followed by cold restraint stress for 30 minutes and cotreated with fluoxetine 10 mg/kg for a period of four weeks. The whole study was done for a period of five weeks followed by behavioural studies and subsequently sacrificed with removal of brain for various histological, Immunohistochemical (IHC), neurochemical and antioxidant analysis. The values were expressed as Mean±SEM. One-way analysis of variance followed by Tukey's multiple comparisons test was used for the comparison of means. A probability of 0.05 and less was taken as statistically significant using Prism Graphpad software version 6.01. The results show there was significant improvement in the Morris water maze test after treatment with fluoxetine in Group 2. Similar results were also noted in the levels of neurotransmitters and antioxidant levels in brain and also in the number of cells counted in IHC and histological studies by H&E when Group 3 was compared with Group 2. The treatment reversed the damage in Group 2 which was comparable with the control group. The results revealed that administration of fluoxetine 10 mg/kg given orally has a potential antistressor effect by improving the neurogenic and neuroprotective effect on the cold restraint stress induced
Fluoxetine regulates cell growth inhibition of interferon-α.

PubMed

Lin, Yu-Min; Yu, Bu-Chin; Chiu, Wen-Tai; Sun, Hung-Yu; Chien, Yu-Chieh; Su, Hui-Chen; Yen, Shu-Yang; Lai, Hsin-Wen; Bai, Chyi-Huey; Young, Kung-Chia; Tsao, Chiung-Wen

2016-10-01

Fluoxetine, a well-known anti-depression agent, may act as a chemosensitizer to assist and promote cancer therapy. However, how fluoxetine regulates cellular signaling to enhance cellular responses against tumor cell growth remains unclear. In the present study, addition of fluoxetine promoted growth inhibition of interferon-alpha (IFN-α) in human bladder carcinoma cells but not in normal uroepithelial cells through lessening the IFN-α-induced apoptosis but switching to cause G1 arrest, and maintaining the IFN-α-mediated reduction in G2/M phase. Activations and signal transducer and transactivator (STAT)-1 and peroxisome proliferator-activated receptor alpha (PPAR-α) were involved in this process. Chemical inhibitions of STAT-1 or PPAR-α partially rescued bladder carcinoma cells from IFN-α-mediated growth inhibition via blockades of G1 arrest, cyclin D1 reduction, p53 downregulation and p27 upregulation in the presence of fluoxetine. However, the functions of both proteins were not involved in the control of fluoxetine over apoptosis and maintained the declined G2/M phase of IFN-α. These results indicated that activation of PPAR-α and STAT-1 participated, at least in part, in growth inhibition of IFN-α in the presence of fluoxetine.
Effect of electrostatic interaction between fluoxetine and lipid membranes on the partitioning of fluoxetine investigated using second derivative spectrophotometry and FTIR.

PubMed

Do, Tien T T; Dao, Uyen P N; Bui, Huong T; Nguyen, Trang T

2017-10-01

The interaction between a drug molecule and lipid bilayers is highly important regarding the pharmaceutical activity of the drug. In this study, the interaction of fluoxetine, a well-known selective serotonin reuptake inhibitor antidepressant and lipid bilayers composed of 1,2-dipalmitoyl-sn-glycero-3-phospho-(1'-rac-glycerol) (DPPG) and 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) was studied from the aspect of electrostatics using second derivative spectrophotometry and Fourier transform infrared spectroscopy (FTIR) in order to provide insights into the drug behavior. Changing pH from 7.4 to 9.5 to increases the neutral state of fluoxetine, the partitioning of fluoxetine into the zwitterionic DPPC large unilamellar vesicles (LUVs) was increased whereas it was reduced into the negatively charged DPPG LUVs. Fluoxetine was found to exhibit a disordering effect on the acyl chains of DPPC and DPPG bilayers upon its partitioning. In addition, increasing concentration of NaCl lessened the binding of fluoxetine into DPPG bilayers due to the reduction in electrostatic attraction between positively charged fluoxetine and negatively charged DPPG LUVs. In addition, the FTIR study revealed that increasing the NaCl concentration could trigger the shift to higher frequency of the CH 2 stretching as well as the notable blue shift in the PO 2 - regions of DPPG, indicating that fluoxetine had deeper penetration into DPPG LUVs. The differences in the NaCl concentration showed a negligible effect on the incorporation of fluoxetine into the zwitterionic DPPC LUVs. In summary, the electrostatic interaction plays an important role on the partitioning of a cationic amphiphilic SSIR drug into the lipid bilayers and the drug partitioning induces the lipids' conformational change. These imply a possible influence on the drug pharmacology. Copyright © 2017 Elsevier B.V. All rights reserved.
Fluoxetine versus other types of pharmacotherapy for depression.

PubMed

Magni, Laura R; Purgato, Marianna; Gastaldon, Chiara; Papola, Davide; Furukawa, Toshi A; Cipriani, Andrea; Barbui, Corrado

2013-07-17

standard form. Responders to treatment were calculated on an intention-to-treat basis: dropouts were always included in this analysis. When data on dropouts were carried forward and included in the efficacy evaluation, they were analysed according to the primary studies; when dropouts were excluded from any assessment in the primary studies, they were considered as treatment failures. Scores from continuous outcomes were analysed by including patients with a final assessment or with the last observation carried forward. Tolerability data were analysed by calculating the proportion of patients who failed to complete the study due to any causes and due to side effects or inefficacy. For dichotomous data, odds ratios (ORs) were calculated with 95% confidence intervals (CI) using the random-effects model. Continuous data were analysed using standardised mean differences (SMD) with 95% CI. A total of 171 studies were included in the analysis (24,868 participants). The included studies were undertaken between 1984 and 2012. Studies had homogenous characteristics in terms of design, intervention and outcome measures. The assessment of quality with the risk of bias tool revealed that the great majority of them failed to report methodological details, like the method of random sequence generation, the allocation concealment and blinding. Moreover, most of the included studies were sponsored by drug companies, so the potential for overestimation of treatment effect due to sponsorship bias should be considered in interpreting the results. Fluoxetine was as effective as the TCAs when considered as a group both on a dichotomous outcome (reduction of at least 50% on the Hamilton Depression Scale) (OR 0.97, 95% CI 0.77 to 1.22, 24 RCTs, 2124 participants) and a continuous outcome (mean scores at the end of the trial or change score on depression measures) (SMD 0.03, 95% CI -0.07 to 0.14, 50 RCTs, 3393 participants). On a dichotomousoutcome, fluoxetine was less effective than dothiepin or
Fluoxetine and imipramine: are there differences in cost-utility for depression in primary care?

PubMed

Serrano-Blanco, Antoni; Suárez, David; Pinto-Meza, Alejandra; Peñarrubia, Maria T; Haro, Josep Maria

2009-02-01

Depressive disorders generate severe personal burden and high economic costs. Cost-utility analyses of the different therapeutical options are crucial to policy-makers and clinicians. Previous cost-utility studies, comparing selective serotonin reuptake inhibitors and tricyclic antidepressants, have used modelling techniques or have not included indirect costs in the economic analyses. To determine the cost-utility of fluoxetine compared with imipramine for treating depressive disorders in primary care. A 6-month randomized prospective naturalistic study comparing fluoxetine with imipramine was conducted in three primary care centres in Spain. One hundred and three patients requiring antidepressant treatment for a DSM-IV depressive disorder were included in the study. Patients were randomized either to fluoxetine (53 patients) or to imipramine (50 patients) treatment. Patients were treated with antidepressants according to their general practitioner's usual clinical practice. Outcome measures were the quality of life tariff of the European Quality of Life Questionnaire: EuroQoL-5D (five domains), direct costs, indirect costs and total costs. Subjects were evaluated at the beginning of treatment and after 1, 3 and 6 months. Incremental cost-utility ratios (ICUR) were obtained. To address uncertainty in the ICUR's sampling distribution, non-parametric bootstrapping was carried out. Taking into account adjusted total costs and incremental quality of life gained, imipramine dominated fluoxetine with 81.5% of the bootstrap replications in the dominance quadrant. Imipramine seems to be a better cost-utility antidepressant option for treating depressive disorders in primary care.
Predictors of Treatment Response to Fluoxetine in PTSD Following a Recent History of War Zone Stress Exposure

DTIC Science & Technology

2009-07-01

First Phase of the Clinical Trial Purchase of the fluoxetine and gelatin capsules from VA pharmacy suppliers (purchased each 3 months throughout the...first 15 months of the study) Over-encapsulation of fluoxetine and empty gelatin capsules by CTVHCS Pharmacy staff Transfer of medications...study. For your own safety, it is your responsibility to tell the doctor all of your past and present diseases, allergies and medical conditions that

Fluoxetine in Treatment of Adolescent Patients with Autism: A Longitudinal Open Trial.

ERIC Educational Resources Information Center

Fatemi, S. Hossein; Realmuto, George M.; Khan, Lubna; Thuras, Paul

1998-01-01

Retrospective chart reviews of seven adolescents and young adults (ages 9-20) with autistic disorder treated with fluoxetine alone or in combination with other medications were performed. Side effects included initial appetite suppression, vivid dreams, and hyperactivity. Improvement was seen in irritability, lethargy, sterotypy, and inappropriate…
From selective to highly selective SSRIs: a comparison of the antinociceptive properties of fluoxetine, fluvoxamine, citalopram and escitalopram.

PubMed

Schreiber, Shaul; Pick, Chaim G

2006-08-01

Most Serotonin Selective Reuptake Inhibitors (SSRIs) have been found to possess secondary binding properties, while citalopram and its S-enantiomer (escitalopram) have been reconfirmed "purest SSRIs". Using the mouse model of acute pain hotplate analgesia meter, we evaluated the antinociceptive properties of fluoxetine, fluvoxamine, citalopram and escitalopram, injected i.p. Fluvoxamine induced a dose-dependent clear antinociceptive effect (with an ED(50) value of 6.4 mg/kg). Both fluoxetine and citalopram induced (separately) only a weak antinociceptive effect with an inverse "U" shape curve. All three drug's effects were not abolished by naloxone. Escitalopram did not elicit any effect at quasi-equipotent doses. These findings show that fluoxetine, fluvoxamine and citalopram given i.p. are weak antinociceptors, (not mediated through opioid mechanisms), while escitalopram possesses no antinociceptive properties when injected i.p. This difference between citalopram and escitalopram calls for further studies in order to assess the various differences between the two enantiomers of citalopram, and between each enantiomer and the racemic mixture.
Metabolic mapping of the effects of the antidepressant fluoxetine on the brains of congenitally helpless rats.

PubMed

Shumake, Jason; Colorado, Rene A; Barrett, Douglas W; Gonzalez-Lima, F

2010-07-09

Antidepressants require adaptive brain changes before efficacy is achieved, and they may impact the affectively disordered brain differently than the normal brain. We previously demonstrated metabolic disturbances in limbic and cortical regions of the congenitally helpless rat, a model of susceptibility to affective disorder, and we wished to test whether administration of fluoxetine would normalize these metabolic differences. Fluoxetine was chosen because it has become a first-line drug for the treatment of affective disorders. We hypothesized that fluoxetine antidepressant effects may be mediated by decreasing metabolism in the habenula and increasing metabolism in the ventral tegmental area. We measured the effects of fluoxetine on forced swim behavior and regional brain cytochrome oxidase activity in congenitally helpless rats treated for 2 weeks with fluoxetine (5mg/kg, i.p., daily). Fluoxetine reduced immobility in the forced swim test as anticipated, but congenitally helpless rats responded in an atypical manner, i.e., increasing climbing without affecting swimming. As hypothesized, fluoxetine reduced metabolism in the habenula and increased metabolism in the ventral tegmental area. In addition, fluoxetine reduced the metabolism of the hippocampal dentate gyrus and dorsomedial prefrontal cortex. This study provided the first detailed mapping of the regional brain effects of an antidepressant drug in congenitally helpless rats. All of the effects were consistent with previous studies that have metabolically mapped the effects of serotonergic antidepressants in the normal rat brain, and were in the predicted direction of metabolic normalization of the congenitally helpless rat for all affected brain regions except the prefrontal cortex. Copyright (c) 2010 Elsevier B.V. All rights reserved.
Predictors of Treatment Response to Fluoxetine in PTSD Following a Recent History of War Zone Stress Exposure

DTIC Science & Technology

2011-07-01

the fluoxetine and gelatin capsules from VA pharmacy suppliers (purchased each 3 months throughout the first 15 months of the study) Over...encapsulation of fluoxetine and empty gelatin capsules by CTVHCS Pharmacy staff Transfer of medications prepared by the CTVHCS Pharmacy directly to the Carl R...associated with the study. For yom own safety, it is your responsibHity to tell the doctor all of your past and present diseases, allergies and medical
Protective effects of melatonin on long-term administration of fluoxetine in rats.

PubMed

Khaksar, Majid; Oryan, Ahmad; Sayyari, Mansour; Rezabakhsh, Aysa; Rahbarghazi, Reza

2017-10-02

The degree and consequence of tissue injury are highly regarded during long-term exposure to selective antidepressant fluoxetine. Melatonin has been shown to palliate different lesions by scavenging free radicals, but its role in the reduction of the fluoxetine-induced injuries has been little known. Thirty-six mature male Wistar rats were randomly assigned into control and experimental groups. The experimental rats were included as following; 24mg/kg/bw fluoxetine for 4 weeks; 1mg/kg/bw melatonin for 4 weeks; fluoxetine+1-week melatonin, fluoxetine+2-week melatonin and fluoxetine+4-week melatonin. In the current experiment, we investigated weight gain, hematological and biochemical parameters, pathological injuries and oxidative status. We noted the positive effect of melatonin in weight loss of fluoxetine-treated rats (p<0.05). The significant reduction of superoxide dismutase, glutathione peroxidase, catalase activities in blood, liver, and kidneys and changes in serum total antioxidant capacity caused by fluoxetine were reversed by melatonin (p<0.05). Melatonin reduced the increased lipid peroxidation and transaminase activity in rats received fluoxetine (p<0.05). We also showed the potency of fluoxetine in inducing leukopenia, thrombocytopenia and hypochromic and macrocytic anemia which was blunted by melatonin. Both RBCs and platelets indices were also corrected. Rats received melatonin in combination with fluoxetine showed a reduction in the severity of degeneration and inflammatory changes in different tissues, brain, heart, liver, lungs, testes and kidneys as compared to the fluoxetine group. Therefore, melatonin fundamentally reversed the side effects of fluoxetine in the rat model which is comparable to human medicine. Copyright © 2017 Elsevier GmbH. All rights reserved.
Fluoxetine for persistent developmental stuttering.

PubMed

Kumar, Amardeep; Balan, Sabish

2007-01-01

Stuttering is a disturbance in the normal fluency and time patterning of speech. Developmental stuttering (DS), with or without associated psychiatric illness, is the most common form and includes all cases with gradual onset in childhood that are not the result of acquired brain damage. Persistent developmental stuttering (PDS) is DS that has not undergone spontaneous or speech therapy-induced remission. Adults in speech therapy behavioral programs will often show regression and even total relapse if they stop practicing. This case report deals with a patient of PDS who responded significantly to treatment with fluoxetine.
Effect of co-administration of fluoxetine and amantadine on immunoendocrine parameters in rats subjected to a forced swimming test.

PubMed

Rogóz, Zofia; Kubera, Marta; Rogóz, Katarzyna; Basta-Kaim, Agnieszka; Budziszewska, Bogusława

2009-01-01

Considerable attention has been paid to a possible role of immunological dysregulation in the pathogenesis of depression. It has been reported that combined administration of antidepressant drugs and the non-competitive NMDA receptor antagonist amantadine reduces immobility time in the forced swimming test (FST). Moreover, preliminary clinical data show that such a combination of drugs has a beneficial effect on treatment-resistant depressed patients. Since immune activation and a pro-inflammatory response are clearly evident in treatment-resistant depression, the aim of the present study was to examine the effect of a combination of the antidepressant fluoxetine and amantadine on immunoendocrine parameters in rats subjected to the forced swimming test. The obtained results revealed synergistic antidepressant effects of the combined administration of fluoxetine (10 mg/kg) and amantadine (10 mg/kg) - drugs otherwise ineffective when given separately in the above doses. Antidepressant activity was accompanied with a significant decrease in the capacity of splenocytes to proliferate in response to concanavalin A. Moerover, fluoxetine and the combination of amantadine and fluoxetine reduced relative spleen weight in rats subjected to the FST, compared to rats treated with the vehicle. The combination of amantadine and fluoxetine enhanced the production of the negative immunoregulator interleukin-10 (but not interferon-gamma) in rats subjected to the FST. The exposure to the FST produced an increase in plasma corticosterone levels, which was significantly attenuated by pretreatment with fluoxetine and amantadine. In summary, the antidepressive efficacy of a combination of fluoxetine and amantadine given in suboptimal doses may be related to the negative immunoendocrine effects of these drugs.
Effect of fluoxetine on disease progression in a mouse model of ALS

PubMed Central

Koschnitzky, J. E.; Quinlan, K. A.; Lukas, T. J.; Kajtaz, E.; Kocevar, E. J.; Mayers, W. F.; Siddique, T.

2014-01-01

Selective serotonin reuptake inhibitors (SSRIs) and other antidepressants are often prescribed to amyotrophic lateral sclerosis (ALS) patients; however, the impact of these prescriptions on ALS disease progression has not been systematically tested. To determine whether SSRIs impact disease progression, fluoxetine (Prozac, 5 or 10 mg/kg) was administered to mutant superoxide dismutase 1 (SOD1) mice during one of three age ranges: neonatal [postnatal day (P)5–11], adult presymptomatic (P30 to end stage), and adult symptomatic (P70 to end stage). Long-term adult fluoxetine treatment (started at either P30 or P70 and continuing until end stage) had no significant effect on disease progression. In contrast, neonatal fluoxetine treatment (P5-11) had two effects. First, all animals (mutant SOD1G93A and control: nontransgenic and SOD1WT) receiving the highest dose (10 mg/kg) had a sustained decrease in weight from P30 onward. Second, the high-dose SOD1G93A mice reached end stage ∼8 days (∼6% decrease in life span) sooner than vehicle and low-dose animals because of an increased rate of motor impairment. Fluoxetine increases synaptic serotonin (5-HT) levels, which is known to increase spinal motoneuron excitability. We confirmed that 5-HT increases spinal motoneuron excitability during this neonatal time period and therefore hypothesized that antagonizing 5-HT receptors during the same time period would improve disease outcome. However, cyproheptadine (1 or 5 mg/kg), a 5-HT receptor antagonist, had no effect on disease progression. These results show that a brief period of antidepressant treatment during a critical time window (the transition from neonatal to juvenile states) can be detrimental in ALS mouse models. PMID:24598527
[Response to serotonergic and noradrenergic antidepressants: a crossover study of fluoxetine and desipramine in patients with first major depression episode].

PubMed

Ontiveros-Sánchez de la Barquera, José Alfonso

2017-01-01

Response rate data from studies with different kinds of antidepressant drugs help in the development of guidelines for the rational prescription of pharmacotherapy. However, there are still few comparative studies with selective reuptake inhibition on serotonin or norepinephrine in the same sample of major depression patients. First episode major depression (DSM-III-R) outpatients who completed 6 weeks in two double-blind randomized trials with fluoxetine and desipramine were crossed over to treatment with the other drug under open conditions for 6 weeks. Response was considered if patient's final Hamilton depression scale score decreased 50% or more from baseline. No significant differences were found by drug treatment or sequence of treatment. Ten of the 18 patients (55.5%) were responders to both fluoxetine and desipramine, 3 (16.6%) were resistant to fluoxetine, 3 (16.6%) to desipramine and 2 (11.1%) to both drugs. These data suggest that among first major depressive episode outpatients fluoxetine and desipramine are equally effective. In patients who have been non-responders to one of the studied drugs, the other one is strikingly effective; this kind of treatment maneuver should be considered in such patients.
Fluoxetine impairs insulin secretion without modifying extracellular serotonin levels in MIN6 β-cells.

PubMed

Cataldo, L R; Cortés, V A; Mizgier, M L; Aranda, E; Mezzano, D; Olmos, P; Galgani, J E; Suazo, J; Santos, J L

2015-09-01

Pancreatic β-cells synthetize and store Serotonin (5-Hydroxytriptamine, 5HT) which is co-released with insulin. It has been proposed that extracellular 5HT binds to specific cell surface receptors and modulate insulin secretion. On the other hand, Selective Serotonin Reuptake Inhibitor (SSRI) fluoxetine seems to reduce Glucose-Stimulated Insulin Secretion (GSIS). However, it is unknown whether this effect results from changes in extracellular 5HT concentration owed to the blockade of 5HT transporter (SERT) or from non-5HT dependent actions. The aims of this work were: 1) to quantify extracellular 5HT levels and GSIS in β-cell lines, 2) to determine whether extracellular 5HT levels and GSIS are changed by fluoxetine or 5-Hydroxytryptophan (5HTP, the immediate 5HT biosynthetic precursor), and 3) to quantify the expression of Slc6a4 gene (encoding SERT) in β-cell lines in relation to other genes involved in 5HT system. β-cell lines MIN6 and RINm5f were subjected to GSIS protocols, after treatment with fluoxetine, 5HTP or 5HT. Insulin and 5HT were quantified by ELISA and HPLC, respectively. Relative mRNA expression was quantified by RT-qPCR. MIN6 β-cells secretes 5HT in response to glucose, showing a sharp increase in 5HT release when cells were preloaded with 5HTP. Treatment with 5HT or fluoxetine reduces GSIS. Fluoxetine fails to further increases 5HTP-induced elevation of secreted 5HT. MIN6 β-cells express both isoforms of Tryptophan Hydroxylase (Tph1 and Tph2), and have high expression levels of L-Dopa decarboxylase (Ddc), both enzymes involved in 5HT biosynthetic pathway, but do not express the 5HT transporters Slc6a4 or Slc6a3 (the Dopamine-5HT transporter) genes. The inhibitory effect of fluoxetine on β-cell glucose stimulated insulin secretion is not mediated by blockage of 5HT transporter through SERT. © Georg Thieme Verlag KG Stuttgart · New York.
Fluoxetine induces autophagic cell death via eEF2K-AMPK-mTOR-ULK complex axis in triple negative breast cancer.

PubMed

Sun, Dejuan; Zhu, Lingjuan; Zhao, Yuqian; Jiang, Yingnan; Chen, Lixia; Yu, Yang; Ouyang, Liang

2018-04-01

Triple negative breast cancer (TNBC) is a complex and intrinsically aggressive tumour with poor prognosis, and the discovery of targeted small-molecule drugs for TNBC treatment still remains in its infancy. In this study, we aimed to discover a small-molecule agent for TNBC treatment and illuminate its potential mechanisms. Cell viability was detected by using methylthiazoltetrazolium (MTT) assay. Electron microscopy, GFP-LC3 transfection, monodansylcadaverine staining and apoptosis assay were performed to determine Fluoxetine-induced autophagy and apoptosis. Western blotting and siRNA transfection were carried out to investigate the mechanisms of Fluoxetine-induced autophagy. iTRAQ-based proteomics analysis was used to explore the underlying mechanisms. We have demonstrated that Fluoxetine had remarkable anti-proliferative activities and induced autophagic cell death in MDA-MB-231 and MDA-MB-436 cells. The mechanism for Fluoxetine-induced autophagic cell death was associated with inhibition of eEF2K and activation of AMPK-mTOR-ULK complex axis. Further iTRAQ-based proteomics and network analyses revealed that Fluoxetine-induced mechanism was involved in BIRC6, BNIP1, SNAP29 and Bif-1. These results demonstrate that Fluoxetine induces apoptosis and autophagic cell death in TNBC, which will hold a promise for the future TNBC therapy. © 2017 John Wiley & Sons Ltd.
Prolonged running, not fluoxetine treatment, increases neurogenesis, but does not alter neuropathology, in the 3xTg mouse model of Alzheimer's disease.

PubMed

Marlatt, Michael W; Potter, Michelle C; Bayer, Thomas A; van Praag, Henriette; Lucassen, Paul J

2013-01-01

Reductions in adult neurogenesis have been documented in the original 3xTg mouse model of Alzheimer's disease (AD), notably occurring at the same age when spatial memory deficits and amyloid plaque pathology appeared. As this suggested reduced neurogenesis was associated with behavioral deficits, we tested whether activity and pharmacological stimulation could prevent memory deficits and modify neurogenesis and/or neuropathology in the 3xTg model backcrossed to the C57Bl/6 strain. We chronically administered the antidepressant fluoxetine to one group of mice, allowed access to a running wheel in another, and combined both treatments in a third cohort. All treatments lasted for 11 months. The female 3xTg mice failed to exhibit any deficits in spatial learning and memory as measured in the Morris water maze, indicating that when backcrossed to the C57Bl/6 strain, the 3xTg mice lost the behavioral phenotype that was present in the original 3xTg mouse maintained on a hybrid background. Despite this, the backcrossed 3xTg mice expressed prominent intraneuronal amyloid beta (Aβ) levels in the cortex and amygdala, with lower levels in the CA1 area of the hippocampus. In the combined cohort, fluoxetine treatment interfered with exercise and reduced the total distance run. The extent of Aβ neuropathology, the tau accumulations, or BDNF levels, were not altered by prolonged exercise. Thus, neuropathology was present but not paralleled by spatial memory deficits in the backcrossed 3xTg mouse model of AD. Prolonged exercise for 11 months did improve the long-term survival of newborn neurons generated during middle-age, whereas fluoxetine had no effect. We further review and discuss the relevant literature in this respect.
Serotonin and histamine mediate gastroprotective effect of fluoxetine against experimentally-induced ulcers in rats.

PubMed

Salem Sokar, Samia; Elsayed Elsayad, Mageda; Sabri Ali, Hend

2016-09-01

Research in the treatment of gastric ulcer has involved the investigation of new alternatives, such as anti-depressant drugs. The present study was designed to investigate the gastroprotective effects of fluoxetine against indomethacin and alcohol induced gastric ulcers in rats and the potential mechanisms of that effect. Fluoxetine (20 mg/kg) was administered IP for 14 days. For comparative purposes, other rats were treated with ranitidine (30 mg/kg). Thereafter, after 24 h of fasting, INDO (100 mg/kg) or absolute alcohol (5 ml/kg) was administered to all rats (saline was administered to naïve controls) and rats in each group were sacrificed 5 h (for INDO rats) or 1 h (for alcohol rats) later. Macroscopic examination revealed that both fluoxetine and ranitidine decreased ulcer scores in variable ratios, which was supported by microscopic histopathological examination. Biochemical analysis of fluoxetine- or ranitidine-pre-treated host tissues demonstrated reductions in tumor necrosis factor (TNF)-α and myeloperoxidase (MPO) levels and concomitant increases in gastric pH, nitric oxide (NO) and reduced glutathione (GSH) contents. Fluoxetine, more than ranitidine, also resulted in serotonin and histamine levels nearest to control values. Moreover, immuno-histochemical analysis showed that fluoxetine markedly enhanced expression of cyclo-oxygenases COX-1 and COX-2 in both models; in comparison, ranitidine did not affect COX-1 expression in either ulcer model but caused moderate increases in COX-2 expression in INDO-induced hosts and high expression in alcohol-induced hosts. The results here indicated fluoxetine exhibited better gastroprotective effects than ranitidine and this could be due to anti-secretory, anti-oxidant, anti-inflammatory and anti-histaminic effects of the drug, as well as a stabilization of gastric serotonin levels.
Local antinociceptive action of fluoxetine in the rat formalin assay: role of l-arginine/nitric oxide/cGMP/KATP channel pathway.

PubMed

Ghorbanzadeh, Behnam; Mansouri, Mohammad Taghi; Naghizadeh, Bahareh; Alboghobeish, Soheila

2018-02-01

The present study was conducted to evaluate the local antinociceptive actions of fluoxetine, a selective serotonin reuptake inhibitor, and the possible involvement of the l-arginine/NO/cGMP/K ATP channel pathway in this effect using the formalin test in rats. To elucidate the underlying mechanisms, animals were pre-treated with l-NAME, aminoguanidine, methylene blue, glibenclamide, l-arginine, sodium nitroprusside, or diazoxide. Local ipsilateral, but not contralateral, administration of fluoxetine (10-300 μg/paw) dose-dependently suppressed flinching number during both early and late phases of the test, and this was comparable with morphine also given peripherally. Pre-treatment with l-NAME, aminoguanidine, methylene blue, or glibenclamide dose-dependently prevented fluoxetine (100 μg/paw)-induced antinociception in the late phase. In contrast, administration of l-arginine, sodium nitroprusside, and diazoxide significantly enhanced the antinociception caused by fluoxetine in the late phase of the test. However, these treatments had no significant effect on the antinociceptive response of fluoxetine in the early phase of the formalin test. Our data demonstrate that local peripheral antinociception of fluoxetine during the late phase of the formalin test could be due to activation of l-arginine/NO/cGMP/K ATP channel pathway. The peripheral action of fluoxetine raises the possibility that topical application of this drug (e.g., as a cream, ointment, or jelly) may be a useful method for relieving the inflammatory pain states.
Fluoxetine pretreatment enhances neurogenic, angiogenic and immunomodulatory effects of MSCs on experimentally induced diabetic neuropathy.

PubMed

Abdelrahman, Shaimaa A; Samak, Mai A; Shalaby, Sally M

2018-04-23

Being one of the most debilitating complications among diabetic patients, diabetic polyneuropathy (DPN) is a paramount point of continuous research. Stem cell therapies have shown promising results. However, limited cell survival and paracrine activities hinder its transfer from bench to bedside. We designed this study to evaluate fluoxetine-pretreatment technique of mesenchymal stem cells (MSCs) as an approach to enhance their paracrine and immunomodulatory properties in DPN. Effects of fluoxetine treatment of MSCs were tested in vitro. Forty-two adult Wistar male albino rats were utilized, further subdivided into control, diabetic, MSC-treated and fluoxetine-pretreated MSC groups. Sciatic nerve sections were prepared for light and electron microscope examination and immunohistochemical detection of neurofilament (NF) protein. Also, we assessed in vitro survival and paracrine properties of fluoxetine-pretreated MSCs. Real time PCR of BDNF, VEGF, IL-1β, and IL-10 expression in tissue homogenate was performed. Our results showed restoration of normal neuronal histomorphology and ultrastructure, moreover, immunohistochemical expression of anti-neurofilament protein was significantly elevated in MSC-treated groups compared to the diabetic one. Fluoxetine enhanced the MSC survival and their paracrine properties of MSCs in vitro. Furthermore, the fluoxetine-pretreated MSC group revealed a significant elevation of mRNA expression of BDNF (neurotrophic factor) and VEGF (angiogenic factor), denoting ameliorated MSC paracrine properties. Similarly, improved immunomodulatory functions were evident by a significant reduction of interleukin-1β mRNA expression (pro-inflammatory) and a reciprocal significant increase of interleukin-10 (anti-inflammatory). We concluded that fluoxetine-pretreatment of MSCs boosts their survival, paracrine, and immunomodulatory traits and directly influenced neuronal histomorphology. Hence, it presents a promising intervention of diabetic
Gastrointestinal Hemorrhage Related to Fluoxetine in a Patient With Stroke.

PubMed

Wee, Tze Chao

2017-11-01

We report on a patient who developed massive gastrointestinal hemorrhage related to the use of fluoxetine in combination with aspirin and clopidogrel. A 58-year-old man was admitted with a posterior circulation infarct with significant weakness in all four limbs and dysarthria. Aspirin and clopidogrel were started. Fluoxetine was started for pharmacological neurostimulation to promote motor recovery and for low mood. He developed gastrointestinal hemorrhage a week after fluoxetine was started. Fluoxetine was suspended and investigations failed to reveal the source of the bleeding. He was then restarted on fluoxetine along with dual antiplatelets, and gastrointestinal hemorrhage recurred after 1 week. He was extensively investigated for a source of gastrointestinal hemorrhage, and again no source could be identified. Eventually, fluoxetine was switched to mirtazapine with no further gastrointestinal hemorrhage. He remained on dual antiplatelets. A number of case-control and cohort studies had identified the association of gastrointestinal hemorrhage with the use of selective serotonin reuptake inhibitor (SSRI). We hope to raise awareness of this association in physical medicine and rehabilitation physicians as the use of SSRI is expected to rise.
Effects of an alkaloid-rich extract from Mitragyna speciosa leaves and fluoxetine on sleep profiles, EEG spectral frequency and ethanol withdrawal symptoms in rats.

PubMed

Cheaha, Dania; Keawpradub, Niwat; Sawangjaroen, Kitja; Phukpattaranont, Pimpimol; Kumarnsit, Ekkasit

2015-10-15

Many antidepressants are effective in alleviating ethanol withdrawal symptoms. However, most of them suppress rapid eye movement (REM) sleep. Thus, development of antidepressants without undesirable side effects would be preferable. Previously, crude alkaloid extract from Mitragyna speciosa (MS) Korth was found to produce antidepressant activities. It was hypothesized that the alkaloid extract from MS may attenuate ethanol withdrawal without REM sleep disturbance. Adult male Wistar rats implanted with electrodes over the frontal and parietal cortices were used for two separated studies. For an acute study, 10 mg/kg fluoxetine or 60 mg/kg alkaloid extract from MS were administered intragastrically. Electroencephalographic (EEG) signals were recorded for 3 h to examine sleep profiles and EEG fingerprints. Another set of animal was used for an ethanol withdrawal study. They were rendered dependent on ethanol via a modified liquid diet (MLD) containing ethanol ad libitum for 28 days. On day 29, fluoxetine (10 mg/kg) or alkaloid extract from MS (60 mg/kg) were administered 15 min before the ethanol-containing MLD was replaced with an isocaloric ethanol-free MLD to induced ethanol withdrawal symptoms. The sleep analysis revealed that alkaloid extract from MS did not change any REM parameters which included average duration of each REM episode, total REM time, number of REM episode and REM latency whereas fluoxetine significantly suppressed all REM parameters and delayed REM latency. However, power spectral analysis revealed similar fingerprints for fluoxetine and alkaloid extract from MS characterized by decreasing powers in the slow frequency range in frontal and parietal cortical EEG. Neither treatment affected spontaneous motor activity. Finally, both alkaloid extract from MS and fluoxetine were found to significantly attenuate ethanol withdrawal-induced hyperexcitability (increases gamma activity) in both cortices and to reduce locomotor activity. The present study
Evaluation of antidepressant like property of amisulpride per se and its comparison with fluoxetine and olanzapine using forced swimming test in albino mice.

PubMed

Pawar, Ganesh R; Agrawal, Rajendra P; Phadnis, Pradeep; Paliwal, Abhay; Vyas, Savita; Solanki, Pooja

2009-01-01

Amisulpride, an atypical antipsychotic was evaluated for antidepressant like activity in forced swimming test in Swiss albino mice. The effect of amisulpride was compared with that of fluoxetine, the standard antidepressant and olanzapine, another atypical antipsychotic claimed to have antidepressant like activity. Both acute and chronic studies were carried out. In both the studies, animals were divided into four groups (n = 8 each) and subjected to oral drug interventions as follows -- Group 1- control (distilled water, 1 mL/kg); Group 2- fluoxetine in a dose of 10 mg/kg 23.5, 5 and 1 h before the test; Group 3-amisulpride in a dose of 70 mg/kg 23.5, 5 and 1 h before the test; Group 4- olanzapine in a dose of 2 mg/kg 23.5, 5 and 1 h before the study. In the chronic study, the treatment was given daily for 28 days with last dose being given 2 h prior to the test. A time sampling method was used to score the behavioral activity in each group. Results of both the studies indicated that animals given amisulpride displayed significant improvement in swimming behavior (p < 0.01), while markedly reducing immobility as compared to control group (p <0.01). Fluoxetine also showed significant difference in activity as compared to amisulpride and olanzapine (p < 0.01). There was no statistically significant difference between amisulpride and olanzapine in terms of effect on immobility and swimming phases in albino mice (p > 0.05). We conclude that amisulpride per se has an antidepressant like activity comparable to that of olanzapine though the activity was significantly less than that of fluoxetine.
Differential effects of fluoxetine and venlafaxine on memory recognition: possible mechanisms of action.

PubMed

Carlini, Valeria Paola; Poretti, María Belén; Rask-Andersen, Mathias; Chavan, Rohit A; Ponzio, Marina F; Sawant, Rahul S; de Barioglio, Susana Rubiales; Schiöth, Helgi B; de Cuneo, Marta Fiol

2012-08-07

Serotonin-specific reuptake inhibitors (SSRI) and serotonin-norepinephrine reuptake inhibitors (SNRI) are antidepressant drugs commonly used to treat a wide spectrum of mood disorders (Wong and Licinio, 2001). Although they have been clinically used for more than 50 years, the molecular and cellular basis for the action of SSRIs and SNRIs is not clear. Considering that the changes in gene expression involved in the action of antidepressant drugs on memory have not been identified, in this study we investigated the impact of chronic treatment with a SSRI (fluoxetine) and a SNRI (venlafaxine) on the mRNA expression of genes related to memory cascade in the mouse hippocampus, namely, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), nitric oxide synthase 1 (NOS1), neurotrophic tyrosine kinase receptor type 2 (TrKB), mitogen-activated protein kinases (MAPK/ERK) and serotonin transporter (SERT). Animals treated with fluoxetine 10 mg/Kg/day for 28 days showed a significant decrease in the percentage of time spent in the novel object recognition test (p≤0.005) and induced MAPK1/ERK2 down-regulation (p=0.005). Our results suggest that the effect on cognition could probably be explained by fluoxetine interference in the MAPK/ERK memory pathway. In contrast, chronic treatment with venlafaxine did not reduce MAPK1/ERK2 expression, suggesting that MAPK1/ERK2 down-regulation is not a common effect of all antidepressant drugs. Further studies are needed to examine the effect of chronic fluoxetine treatment on the ERK-CREB system, and to determine whether there is a causal relationship between the disruption of the ERK-CREB system and the effect of this antidepressant on memory performance. Copyright © 2012 Elsevier Inc. All rights reserved.
Pharmacokinetics of Fluoxetine in Pregnant Baboons (Papio spp.)

PubMed Central

Shoulson, Rivka L; Stark, Raymond L; Garland, Marianne

2014-01-01

Fluoxetine is used to treat a number of psychiatric conditions in humans and behavioral problems in animals. Its use in pregnancy must balance maternal benefit with potential risk to the fetus. Knowledge of adult and fetal drug disposition can assist clinicians in selecting therapy that minimizes adverse effects to the fetus. Nonhuman primate models are used frequently in drug dose-translation studies, and pregnancy in baboons has many similarities to human pregnancy. Accordingly, pharmacokinetic analysis of a series of fluoxetine and norfluoxetine administrations to pregnant baboons was performed. The mean maternal baboon steady-state clearance of fluoxetine (42 mL/min/kg) was considerably higher than that in humans. Norfluoxetine, the major active metabolite, had a higher metabolite-to-drug ratio (8.7) than that found in humans, particularly with oral dosing. These results are consistent with more extensive metabolism in baboons than in humans and leads to a higher clearance than would be expected from allometric scaling. Fetal-to-maternal fluoxetine and norfluoxetine ratios under steady-state conditions were similar to those in humans, with fetal concentrations of fluoxetine 42% and norfluoxetine 47% of maternal concentrations. The fetal clearance of fluoxetine (303 ± 176 mL/min) and norfluoxetine (450 mL/min) exceeded reported placental blood flow. Understanding these species-associated differences in metabolism is a prerequisite to extrapolating data between species. Nonetheless, nonhuman primates are likely to remain valuable models for pharmacokinetic studies during pregnancy, particularly those directed toward fetal neurodevelopmental effects. Our results also are applicable to determining appropriate dosing of nonhuman primates in clinical settings. PMID:25650979

Hippocampal HDAC4 contributes to postnatal fluoxetine-evoked depression-like behavior.

PubMed

Sarkar, Ambalika; Chachra, Parul; Kennedy, Pamela; Pena, Catherine J; Desouza, Lynette A; Nestler, Eric J; Vaidya, Vidita A

2014-08-01

Fluoxetine treatment in adulthood evokes antidepressant and anxiolytic responses. Paradoxically, postnatal fluoxetine (PNFlx) induces persistent depression- and anxiety-like behaviors. The mechanistic underpinnings of this paradox remain poorly understood. Here, we examined specific molecular changes in the rat hippocampus that accompany perturbed emotionality observed across life following PNFlx. PNFlx-induced hippocampal gene regulation observed in microarray and quantitative PCR studies indicate functional enrichment of genes involved in response to organic substances, protein kinase pathways, DNA binding, and transcriptional repression. We noted specific transcripts (Hdac4, mammalian target of rapamycin (mTOR), Gnai1, protein kinase C gamma (Prkcc), and hyperpolarization-activated cyclic nucleotide-gated channel 1 (Hcn1)) that were consistently dysregulated across life, and selectively influenced by postnatal, but not adult, fluoxetine. Increased histone deacetylase-4 (HDAC4) recruitment, accompanied by decreased activating histone acetylation marks at the mTOR and Gnai1 promoters, indicate a role for HDAC4 in PNFlx-mediated gene dysregulation. Strikingly, coadministration of the HDAC inhibitor sodium butyrate with PNFlx prevented the dysregulation of Hdac4 and mTOR, and the emergence of depression- and anxiety-like behavior. Importantly, we also find that retreatment of PNFlx animals with fluoxetine in adulthood reversed the increased Hdac4 expression, prevented HDAC4 recruitment to the mTOR and Gnai1 promoters, and attenuated the decline in mTOR and Gnai1 expression, coincident with normalization of PNFlx-evoked depression- and anxiety-like behavior. Further, we show that viral-mediated hippocampal overexpression of Hdac4 was sufficient to induce depression-, but not anxiety-, like behavior in adulthood. Our results highlight the unique nature of molecular signatures evoked by PNFlx, and implicate HDAC4 in the dysregulated gene expression and emergence of
Comparison between herbal medicine and fluoxetine for depression: a systematic review of randomized controlled trials.

PubMed

Ren, Yi; Zhu, Chenjun; Wu, Jianjun; Zheng, Ruwen; Cao, Huijaun

2015-10-01

To evaluate the effectiveness and safety of Chinese herbal medicine (CHM) versus fluoxetine on depression. A systematic review of randomized controlled trials (RCTs). RCT with two parallel groups that compared CHM and fluoxetine on treatment of depression with reported decreased Hamilton Depression Scale (HAMD) and adverse events during treatment were included after searching through six electric-databases. The methodological quality of RCTs was assessed according to the Cochrane risk of bias tool. Meta-analysis was conducted using RevMan 5.3 software with pooled mean difference (MD) or risk ratio (RR) and their 95% confidence interval (CI) if no significant heterogeneity was detected. A SOF table was generated using GRADEPro software to evaluate the overall quality of the evidence. Twenty-six trials with 3294 participants were included in the review. Most of them had high risk of bias during conducting and reporting. The results achieved weak evidence which showed CHM had similar effect to fluoxetine (20mg/day) on relieving depression according to HAMD assessment (for primary depression: MD=-0.08, 95%CI -0.98-0.82; for secondary depression: MD=-0.36, 95%CI -1.55-0.83), but fewer incidences of adverse events than the drug (for primary depression: RR=0.31, 95%CI 0.17-0.59; for post-stroke depression: RR=0.04, 95%CI 0.00-0.25). No serious adverse event was found in neither CHM nor fluoxetine group. Due to the poor quality of included trials and the potential publication bias of this review, no confirmed conclusion could be draw to evaluate the effectiveness and safety of CHM for depression compared with fluoxetine. Copyright © 2015 Elsevier Ltd. All rights reserved.
Long-lasting effects of fluoxetine and/or exercise augmentation on bio-behavioural markers of depression in pre-pubertal stress sensitive rats.

PubMed

Schoeman, Jacobus C; Steyn, Stephanus F; Harvey, Brian H; Brink, Christiaan B

2017-04-14

Juvenile depression is of great concern with only limited treatment currently approved. Delayed onset of action, low remission and high relapse rates, and potential long-lasting consequences further complicates treatment and highlights the need for new treatment options. Studies reporting on long-lasting effects of early-life treatment have reported conflicting results, with the pre-adolescent period mostly overlooked. The anti-depressive effect of exercise, as a possible treatment option or augmentation strategy, is dependent on age and exercise intensity. We investigated the immediate (i.e. postnatal day 35 (PND35)) and lasting (PND60 to PND61) effects of pre-pubertal (PND21 to PND34) fluoxetine and/or exercise on bio-behavioural markers of depression and oxidative stress in stress sensitive Flinders Sensitive Line rats. Low, but not moderate, intensity exercise or 5, but not 10, mg/kg/day fluoxetine displayed anti-depressant-like properties at PND35. Pre-pubertal treatment with 5mg/kg/day fluoxetine or low intensity exercise exerted lasting anti-depressive-like effects into adulthood, whereas the combination of these two treatments did not. Furthermore, the combination of fluoxetine plus exercise reduced hippocampal BDNF levels as compared to exercise alone, which may explain the latter findings. In all treatment groups hippocampal SOD activity was significantly increased at PND61, suggesting an increased anti-oxidant capacity in adulthood. In conclusion, the data confirm the anti-depressant-like properties of both early-life fluoxetine and exercise in a genetic animal model of depression. However, optimal lasting effects of early-life interventions may require adjustment of antidepressant dose and/or exercise intensity to developmental age, and that a combination of antidepressant and exercise may not necessarily be augmentative. Copyright © 2017 Elsevier B.V. All rights reserved.
Up-regulation of melanin synthesis by the antidepressant fluoxetine.

PubMed

Liao, Sha; Shang, Jing; Tian, Xiaoli; Fan, Xueqi; Shi, Xiupu; Pei, Siran; Wang, Qian; Yu, Boyang

2012-08-01

Fluoxetine, a member of the class of selective serotonin reuptake inhibitors, is a potent antidepressant commonly used in clinical practice. Here, we report that fluoxetine increases cellular tyrosinase (TYR) activity, enhances the protein levels of microphthalmia-associated transcription factor (MITF), TYR and tyrosinase-related protein-1 (TRP-1) and eventually leads to a dramatic increase in melanin production in both murine B16F10 melanoma cells and normal human melanocytes (NHMCs). In well-characterized C57BL/6 mouse models, systemic application of fluoxetine increased hair pigmentation by up-regulating hair follicular MITF, TYR, TRP-1 and tyrosinase-related protein-2 (TRP-2) protein levels. Using a serotonin 1A receptor (SR1A) antagonist and RNA interference (RNAi) technique, we revealed that SR1A appears to be one of the involved pathways in the fluoxetine-induced melanogenesis in B16F10 cells. These results suggest that fluoxetine may hold a significant therapeutic potential for treating skin hypopigmentation disorders, and SR1A may serve as a novel target in modulating melanogenesis. © 2012 John Wiley & Sons A/S.
Determination of fluoxetine in Dermestes maculatus (Coleoptera: Dermestidae) by a spectrophotometric method.

PubMed

Zanetti, Noelia I; Ferrero, Adriana A; Centeno, Néstor D

2016-12-01

The aims of this study were to detect and quantify fluoxetine, an antidepressant, from entomological samples. Larvae, pupae and adults of Dermestes maculatus (Coleoptera, Dermestidae) were reared on pig muscle previously treated with fluoxetine. The concentration selected, 2000mg/kg, emulates a fluoxetine overdose lethal to humans and laboratory animals. Thirty larvae on the fourth and fifth stages, 50 adults and several exuviae were analyzed for fluoxetine content. Detection of fluoxetine was performed by UV spectrophotometry at 270 and 277nm. All developmental stages of D. maculatus and exuviae were positive for fluoxetine. We also quantified the drug and no significant differences were found either between the days or the stages in the general model, but at 277nm a tendency of the concentration to decrease with time was observed. Concentrations of fluoxetine at 277nm were almost equal or greater than those at 270nm. This is the first study to detect and quantify fluoxetine from entomological samples and, in particular, from D. maculatus beetles. Copyright Â© 2016 The Chartered Society of Forensic Sciences. Published by Elsevier Ireland Ltd. All rights reserved.
Fluoxetine exposure impacts boldness in female Siamese fighting fish, Betta splendens.

PubMed

Dzieweczynski, Teresa L; Kane, Jessica L; Campbell, Brennah A; Lavin, Lindsey E

2016-01-01

The present study examined the effects of the selective serotonin reuptake inhibitor, fluoxetine, on the behavior of female Siamese fighting fish, Betta splendens, in three different boldness assays (Empty Tank, Novel Environment, Social Tendency). When females were unexposed to fluoxetine, boldness was consistent within a context and correlated across assays. Fluoxetine exposure affected behavior within and among individuals on multiple levels. Exposure reduced overall boldness levels, made females behave in a less consistent manner, and significantly reduced correlations over time and across contexts. Fluoxetine exerted its effects on female Betta splendens behavior in a dose-dependent fashion and these effects persisted even after females were housed in clean water. If fluoxetine exposure impacts behaviors such as exploration that are necessary to an individual’s success, this may yield evolutionary consequences. In conclusion, the results show that fluoxetine exposure alters behavior beyond the level of overall response and highlights the importance of studying the behavioral effects of inadvertent pharmaceutical exposure in multiple contexts and with different dosing regimes.
Bi-phasic regulation of glycogen content in astrocytes via Cav-1/PTEN/PI3K/AKT/GSK-3β pathway by fluoxetine.

PubMed

Bai, Qiufang; Song, Dan; Gu, Li; Verkhratsky, Alexei; Peng, Liang

2017-04-01

Here, we present the data indicating that chronic treatment with fluoxetine regulates Cav-1/PTEN/PI3K/AKT/GSK-3β signalling pathway and glycogen content in primary cultures of astrocytes with bi-phasic concentration dependence. At lower concentrations, fluoxetine downregulates gene expression of Cav-1, decreases membrane content of PTEN, increases activity of PI3K/AKT, and elevates GSK-3β phosphorylation thus suppressing its activity. At higher concentrations, fluoxetine acts in an inverse fashion. As expected, fluoxetine at lower concentrations increased while at higher concentrations decreased glycogen content in astrocytes. Our findings indicate that bi-phasic regulation of glycogen content via Cav-1/PTEN/PI3K/AKT/GSK-3β pathway by fluoxetine may be responsible for both therapeutic and side effects of the drug.
Ecotoxicological assessments show sucralose and fluoxetine affect the aquatic plant, Lemna minor.

PubMed

Amy-Sagers, Cherisse; Reinhardt, Keith; Larson, Danelle M

2017-04-01

Pharmaceuticals and personal care products (PPCP) are prevalent in aquatic systems, yet the fate and impacts on aquatic plants needs quantification for many compounds. We measured and detected sucralose (an artificial sweetener), fluoxetine (an antidepressant), and other PPCP in the Portneuf River in Idaho, USA, where Lemna minor (an aquatic plant in the environment and used in ecotoxicology studies) naturally occurs. Sucralose was hypothesized to negatively affect photosynthesis and growth of L. minor because sucralose is a chlorinated molecule that may be toxic or unusable for plant metabolism. A priori hypotheses were not created for fluoxetine due to lack of previous studies examining its impacts on plants. We conducted laboratory ecotoxicological assessments for a large range of concentrations of sucralose and fluoxetine on L. minor physiology and photosynthetic function. Frond green leaf area, root length, growth rate, photosynthetic capacity, and plant carbon isotopic composition (discrimination relative to a standard; δ 13 C) were measured among treatments ranging from 0 to 15000nmol/L-sucralose and 0-323nmol/L-fluoxetine. Contrary to our predictions, sucralose significantly increased green leaf area, photosynthetic capacity, and δ 13 C of L. minor at environmentally relevant concentrations. The increase of δ 13 C from sucralose amendments and an isotope-mixing model indicated substantial sucralose uptake and assimilation within the plant. Unlike humans who cannot break down and utilize sucralose, we documented that L. minor-a mixotrophic plant-can use sucralose as a sugar substitute to increase its green leaf area and photosynthetic capacity. Fluoxetine significantly decreased L. minor root growth, daily growth rate, and asexual reproduction at 323nmol/L-fluoxetine; however, ambiguity remains regarding the mechanisms responsible and the applicability of these extreme concentrations unprecedented in the natural environment. To our knowledge, this was the
No effect of C1473G polymorphism in the tryptophan hydroxylase 2 gene on the response of the brain serotonin system to chronic fluoxetine treatment in mice.

PubMed

Bazhenova, Ekaterina Y; Sinyakova, Nadezhda A; Kulikova, Elizabeth A; Kazarinova, Irina A; Bazovkina, Daria V; Gainetdinov, Raul R; Kulikov, Alexander V

2017-07-13

Selective serotonin reuptake inhibitors (SSRIs) are antidepressants that block serotonin transporter (SERT) and increase serotonin (5-HT) level in the synaptic cleft. The interaction between SERT and the key enzyme of 5-HT synthesis in the brain, tryptophan hydroxylase 2 (TPH2), is essential to maintain the brain 5-HT level. The G allele of C1473G polymorphism in Tph2 gene decreases enzyme activity by half in mouse brain. Here we studied effect of C1473G polymorphism on the reaction of brain 5-HT system to chronic fluoxetine treatment (120mg/l in drinking water, for 3 weeks) in adult males of the congenic B6-1473C and B6-1473G mouse lines with high and low enzyme activity, respectively. The polymorphism did not affect the levels of 5-HT, its metabolite, 5-hydroxyindoleacetic acid (5-HIAA) and Tph2 gene mRNA in the brain. Fluoxetine significantly attenuated 5-HT levels in the cortex and striatum, 5-HIAA concentrations in the cortex, hippocampus, striatum and midbrain, and Tph2 gene expression in the midbrain. However, we did not observed any effect of the genotype x treatment interaction on these neurochemical characteristics. Therefore, C1473G polymorphism does not seem to play an essential role in the reaction of the brain 5-HT system to chronic fluoxetine treatment. Copyright © 2017 Elsevier B.V. All rights reserved.
Chronic fluoxetine treatment directs energy metabolism towards the citric acid cycle and oxidative phosphorylation in rat hippocampal nonsynaptic mitochondria.

PubMed

Filipović, Dragana; Costina, Victor; Perić, Ivana; Stanisavljević, Andrijana; Findeisen, Peter

2017-03-15

Fluoxetine (Flx) is the principal treatment for depression; however, the precise mechanisms of its actions remain elusive. Our aim was to identify protein expression changes within rat hippocampus regulated by chronic Flx treatment versus vehicle-controls using proteomics. Fluoxetine-hydrohloride (15mg/kg) was administered daily to adult male Wistar rats for 3weeks, and cytosolic and nonsynaptic mitochondrial hippocampal proteomes were analyzed. All differentially expressed proteins were functionally annotated according to biological process and molecular function using Uniprot and Blast2GO. Our comparative study revealed that in cytosolic and nonsynaptic mitochondrial fractions, 60 and 3 proteins respectively, were down-regulated, and 23 and 60 proteins, respectively, were up-regulated. Proteins differentially regulated in cytosolic and nonsynaptic mitochondrial fractions were primarily related to cellular and metabolic processes. Of the identified proteins, the expressions of calretinin and parvalbumine were confirmed. The predominant molecular functions of differentially expressed proteins in both cell hippocampal fractions were binding and catalytic activity. Most differentially expressed proteins in nonsynaptic mitochondria were catalytic enzymes involved in the pyruvate metabolism, citric acid cycle, oxidative phosphorylation, ATP synthesis, ATP transduction and glutamate metabolism. Results indicate that chronic Flx treatment may influence proteins involved in calcium signaling, cytoskeletal structure, chaperone system and stimulates energy metabolism via the upregulation of GAPDH expression in cytoplasm, as well as directing energy metabolism toward the citric acid cycle and oxidative phosphorylation in nonsynaptic mitochondria. This approach provides new insight into the chronic effects of Flx treatment on protein expression in a key brain region associated with stress response and memory. Copyright Â© 2017 Elsevier B.V. All rights reserved.
Fluoxetine during development reverses the effects of prenatal stress on depressive-like behavior and hippocampal neurogenesis in adolescence.

PubMed

Rayen, Ine; van den Hove, Daniël L; Prickaerts, Jos; Steinbusch, Harry W; Pawluski, Jodi L

2011-01-01

Depression during pregnancy and the postpartum period is a growing health problem, which affects up to 20% of women. Currently, selective serotonin reuptake inhibitor (SSRIs) medications are commonly used for treatment of maternal depression. Unfortunately, there is very little research on the long-term effect of maternal depression and perinatal SSRI exposure on offspring development. Therefore, the aim of this study was to determine the role of exposure to fluoxetine during development on affective-like behaviors and hippocampal neurogenesis in adolescent offspring in a rodent model of maternal depression. To do this, gestationally stressed and non-stressed Sprague-Dawley rat dams were treated with either fluoxetine (5 mg/kg/day) or vehicle beginning on postnatal day 1 (P1). Adolescent male and female offspring were divided into 4 groups: 1) prenatal stress+fluoxetine exposure, 2) prenatal stress+vehicle, 3) fluoxetine exposure alone, and 4) vehicle alone. Adolescent offspring were assessed for anxiety-like behavior using the Open Field Test and depressive-like behavior using the Forced Swim Test. Brains were analyzed for endogenous markers of hippocampal neurogenesis via immunohistochemistry. Results demonstrate that maternal fluoxetine exposure reverses the reduction in immobility evident in prenatally stressed adolescent offspring. In addition, maternal fluoxetine exposure reverses the decrease in hippocampal cell proliferation and neurogenesis in maternally stressed adolescent offspring. This research provides important evidence on the long-term effect of fluoxetine exposure during development in a model of maternal adversity.
A double-blind efficacy and safety study of duloxetine flexible dosing in children and adolescents with major depressive disorder.

PubMed

Atkinson, Sarah D; Prakash, Apurva; Zhang, Qi; Pangallo, Beth A; Bangs, Mark E; Emslie, Graham J; March, John S

2014-05-01

The purpose of this study was to evaluate the efficacy and safety of duloxetine flexible dose in children (7-11 years) and adolescents (12-17 years) with major depressive disorder (MDD). Patients (n=337) in this 36 week study (10 week acute and 26 week extension treatment) received duloxetine (60-120 mg once daily [QD], n=117), fluoxetine (20-40 mg QD, n=117), or placebo (n=103). Measures included: Children's Depression Rating Scale-Revised (CDRS-R), treatment-emergent adverse events (TEAEs), and Columbia-Suicide Severity Rating Scale (C-SSRS). Neither active drug (duloxetine or fluoxetine) separated significantly (p<0.05) from placebo on mean change from baseline to end-point (10 weeks) on the CDRS-R total score. There were no significant differences between the duloxetine or fluoxetine groups compared with placebo on serious AEs (SAEs), total TEAEs, or discontinuation for AE during acute treatment. There were no completed suicides or deaths, and no clinically significant electrocardiogram (ECG) abnormalities observed during the study. One fluoxetine and one duloxetine patient experienced alanine aminotransferase (ALT) three or more times the upper limit of normal, which resolved during the study. A total of 8 (7.1%) duloxetine patients, 7 (6.8%) placebo patients, and 9 (8.0%) fluoxetine patients had worsening of suicidal ideation from baseline during acute treatment. Of the patients with suicidal ideation at baseline, 15/19 (79%) duloxetine, 19/19 (100%) placebo, and 16/19 (84%) fluoxetine had improvement in suicidal ideation at end-point during acute treatment. One duloxetine and two fluoxetine patients had treatment-emergent suicidal behavior during the 36 week study. Trial results were inconclusive, as neither the investigational drug (duloxetine) nor the active control (fluoxetine) separated from placebo on the CDRS-R at 10 weeks. No new duloxetine safety signals were identified relative to those seen in adults. Clinical Trial Registry Number: NCT00849901.
Antidepressant effects of combination of brexpiprazole and fluoxetine on depression-like behavior and dendritic changes in mice after inflammation.

PubMed

Ma, Min; Ren, Qian; Yang, Chun; Zhang, Ji-Chun; Yao, Wei; Dong, Chao; Ohgi, Yuta; Futamura, Takashi; Hashimoto, Kenji

2017-02-01

Addition of low doses of atypical antipsychotic drugs with selective serotonin reuptake inhibitors (SSRIs) could promote a rapid antidepressant effect in treatment-resistant patients with major depression. Brexpiprazole, a new atypical antipsychotic drug, has been used as adjunctive therapy for the treatment of major depression. The present study was undertaken to examine whether brexpiprazole could augment antidepressant effects of the SSRI fluoxetine in an inflammation model of depression. We examined the effects of fluoxetine (10 mg/kg), brexpiprazole (0.1 mg/kg), or the combination of the two drugs on depression-like behavior, alterations in the brain-derived neurotrophic factor (BDNF) - TrkB signaling, and dendritic spine density in selected brain regions after administration of lipopolysaccharide (LPS) (0.5 mg/kg). Combination of brexpiprazole and fluoxetine promoted a rapid antidepressant effect in inflammation model although brexpipazole or fluoxetine alone did not show antidepressant effect. Furthermore, the combination significantly improved LPS-induced alterations in the BDNF - TrkB signaling and dendritic spine density in the prefrontal cortex, CA3 and dentate gyrus, and nucleus accumbens. These results suggest that add-on of brexpiprazole to fluoxetine can produce a rapid antidepressant effect in the LPS inflammation model of depression, indicating that adjunctive therapy of brexpiprazole to SSRIs could produce a rapid antidepressant effect in depressed patients with inflammation.
Fluoxetine (Prozac) and Pregnancy

MedlinePlus

... pregnancy complications can be related to the maternal depressive disorder itself rather than to the medication exposure. One study showed that babies whose mothers take SSRIs like fluoxetine during the second half ...
Fluoxetine, an antidepressant, suppresses glioblastoma by evoking AMPAR-mediated calcium-dependent apoptosis

PubMed Central

Liu, Kao-Hui; Yang, Shun-Tai; Lin, Yen-Kuang; Lin, Jia-Wei; Lee, Yi-Hsuan; Wang, Jia-Yi; Hu, Chaur-Jong; Lin, En-Yuan; Chen, Shu-Mei; Then, Chee-Kin; Shen, Shing-Chuan

2015-01-01

The efficacy of glioblastoma chemotherapy is not satisfactory; therefore, a new medication is expected to improve outcomes. As much evidence shows that antidepressants decrease cancer incidence and improve patients' quality of life, we therefore attempted to explore the potential for fluoxetine to be used to treat GBM and its possible underlying mechanism. The expression level of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) was determined using immunohistochemical staining and PCR analysis. The mechanism of fluoxetine-induced apoptosis of gliomas was elucidated. Computer modeling and a binding assay were conducted to investigate the interaction of fluoxetine with the AMPAR. The therapeutic effect of fluoxetine was evaluated using an animal model. We found that fluoxetine directly bound to AMPAR, thus inducing transmembrane Ca2+ influx. The rise in the intracellular calcium concentration ([Ca2+]i) causes mitochondrial Ca2+ overload, thereby triggering apoptosis. AMPARs are excessively expressed in glioma tissues, suggesting that fluoxetine specifically executes glioma cells. Our in vivo study revealed that fluoxetine suppressed the growth of glioblastomas in brains of Nu/Nu mice, an effect similar to that produced by temozolomide. Our preclinical studies suggest fluoxetine, a commonly used antidepressant, might be selectively toxic to gliomas and could provide a new approach for managing this disease. PMID:25671301
Paroxetine and fluoxetine in pregnancy: a prospective, multicentre, controlled, observational study

PubMed Central

Diav-Citrin, Orna; Shechtman, Svetlana; Weinbaum, Dafna; Wajnberg, Rebecka; Avgil, Meytal; Di Gianantonio, Elena; Clementi, Maurizio; Weber-Schoendorfer, Corinna; Schaefer, Christof; Ornoy, Asher

2008-01-01

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT In recent years there has been concern regarding the possibility that selective serotonin reuptake inhibitors (SSRIs) cause an increased rate of congenital cardiovascular anomalies. As of today, there is still debate in the literature as to the possible effects of paroxetine and fluoxetine on the embryonic cardiovascular system. WHAT THIS STUDY ADDS Based on prospective data from three Teratogen Information Services, we have demonstrated an increased rate of congenital cardiovascular anomalies among the offspring of fluoxetine- and paroxetine-treated mothers. AIMS Recent studies have suggested a possible association between maternal use of selective serotonin reuptake inhibitors (SSRIs) in early pregnancy and cardiovascular anomalies. The aim of the present study was to evaluate the teratogenic risk of paroxetine and fluoxetine. METHODS This multicentre, prospective, controlled study evaluated the rate of major congenital anomalies after first-trimester gestational exposure to paroxetine, fluoxetine or nonteratogens. RESULTS We followed up 410 paroxetine, 314 fluoxetine first-trimester exposed pregnancies and 1467 controls. After exclusion of genetic and cytogenetic anomalies, there was a higher rate of major anomalies in the SSRI groups compared with the controls [paroxetine 18/348 (5.2%), fluoxetine 12/253 (4.7%) and controls 34/1359 (2.5%)]. The main risk applied to cardiovascular anomalies [paroxetine 7/348 (2.0%), crude odds ratio (OR) 3.47, 95% confidence interval (CI) 1.13, 10.58; fluoxetine 7/253 (2.8%), crude OR, 4.81 95% CI 1.56, 14.71; and controls 8/1359 (0.6%)]. On logistic regression analysis only cigarette smoking of ≥10 cigarettes day−1 and fluoxetine exposure were significant variables for cardiovascular anomalies. The adjusted ORs for paroxetine and fluoxetine were 2.66 (95% CI 0.80, 8.90) and 4.47 (95% CI 1.31, 15.27), respectively. CONCLUSION This study suggests a possible association between
Forced swimming test and fluoxetine treatment: in vivo evidence that peripheral 5-HT in rat platelet-rich plasma mirrors cerebral extracellular 5-HT levels, whilst 5-HT in isolated platelets mirrors neuronal 5-HT changes.

PubMed

Bianchi, M; Moser, C; Lazzarini, C; Vecchiato, E; Crespi, F

2002-03-01

Low levels of central serotonin (5-HT) have been related to the state of depression, and 5-HT is the major target of the newer antidepressant drugs such as selective serotonin reuptake inhibitors (SSRIs). Neurons and platelets display structural and functional similarities, so that the latter have been proposed as a peripheral model of central functions. In particular, in blood more than 99% of 5-HT is contained in platelets, so that one could consider changes in 5-HT levels in platelets as a mirror of changes in central 5-HT. Here, this hypothesis has been studied via the analysis of the influence of: (1) the forced swimming test (FST, which has been proved to be of utility to predict the clinical efficacy of antidepressants in rodents) and (2) treatment with the SSRI fluoxetine upon 5-HT levels monitored in brain regions and in peripheral platelets by means of electrochemical in vivo and ex vivo measurements. The results obtained confirm that the FST increases immobility; furthermore they show a parallel and significant decrease in cerebral (brain homogenate) and peripheral (in platelet-rich plasma, PRP) voltammetric 5-HT levels following the FST in naive rats. In addition, subchronic treatment with fluoxetine was followed by a significant increase in 5-HT levels in PRP, while the same SSRI treatment performed within the FST resulted in a decrease in the 5-HT levels in PRP. However, this decrease was inferior to that observed without SSRI treatment. These data suggest that there is an inverse relationship between immobility and the levels of 5-HT in PRP and that these peripheral 5-HT levels are sensitive to: (1) the FST, (2) the treatment with fluoxetine and (3) the combination of both treatments, i.e. SSRI + FST. It has been reported that SSRI treatment at first inhibits the 5-HT transporter in brain, resulting in increased extracellular 5-HT, while following sustained SSRI treatments decreased intracellular levels of central 5-HT were observed. Accordingly, the
Fluoxetine Decreases the Proliferation and Adipogenic Differentiation of Human Adipose-Derived Stem Cells

PubMed Central

Sun, Bo Kyung; Kim, Ji Hye; Choi, Joon-Seok; Hwang, Sung-Joo; Sung, Jong-Hyuk

2015-01-01

Fluoxetine was originally developed as an antidepressant, but it has also been used to treat obesity. Although the anti-appetite effect of fluoxetine is well-documented, its potential effects on human adipose-derived stem cells (ASCs) or mature adipocytes have not been investigated. Therefore, we investigated the mechanisms underlying the inhibitory effects of fluoxetine on the proliferation of ASCs. We also investigated its inhibitory effect on adipogenic differentiation. Fluoxetine significantly decreased ASC proliferation, and signal transduction PCR array analysis showed that it increased expression of autophagy-related genes. In addition, fluoxetine up-regulated SQSTM1 and LC3B protein expression as detected by western blotting and immunofluorescence. The autophagy inhibitor, 3-methyladenine (3-MA), significantly attenuated fluoxetine-mediated effects on ASC proliferation and SQSTM1/LC3B expression. In addition, 3-MA decreased the mRNA expression of two autophagy-related genes, beclin-1 and Atg7, in ASCs. Fluoxetine also significantly inhibited lipid accumulation and down-regulated the levels of PPAR-γ and C/EBP-α in ASCs. Collectively, these results indicate that fluoxetine decreases ASC proliferation and adipogenic differentiation. This is the first in vitro evidence that fluoxetine can reduce fat accumulation by inhibiting ASC proliferation and differentiation. PMID:26204837
Fluoxetine Decreases the Proliferation and Adipogenic Differentiation of Human Adipose-Derived Stem Cells.

PubMed

Sun, Bo Kyung; Kim, Ji Hye; Choi, Joon-Seok; Hwang, Sung-Joo; Sung, Jong-Hyuk

2015-07-22

Fluoxetine was originally developed as an antidepressant, but it has also been used to treat obesity. Although the anti-appetite effect of fluoxetine is well-documented, its potential effects on human adipose-derived stem cells (ASCs) or mature adipocytes have not been investigated. Therefore, we investigated the mechanisms underlying the inhibitory effects of fluoxetine on the proliferation of ASCs. We also investigated its inhibitory effect on adipogenic differentiation. Fluoxetine significantly decreased ASC proliferation, and signal transduction PCR array analysis showed that it increased expression of autophagy-related genes. In addition, fluoxetine up-regulated SQSTM1 and LC3B protein expression as detected by western blotting and immunofluorescence. The autophagy inhibitor, 3-methyladenine (3-MA), significantly attenuated fluoxetine-mediated effects on ASC proliferation and SQSTM1/LC3B expression. In addition, 3-MA decreased the mRNA expression of two autophagy-related genes, beclin-1 and Atg7, in ASCs. Fluoxetine also significantly inhibited lipid accumulation and down-regulated the levels of PPAR-γ and C/EBP-α in ASCs. Collectively, these results indicate that fluoxetine decreases ASC proliferation and adipogenic differentiation. This is the first in vitro evidence that fluoxetine can reduce fat accumulation by inhibiting ASC proliferation and differentiation.
BiteStrip analysis of the effect of fluoxetine and paroxetine on sleep bruxism.

PubMed

Isa Kara, M; Ertaş, Elif Tarım; Ozen, Emrullah; Atıcı, Meral; Aksoy, Selami; Erdogan, Muharrem Serif; Kelebek, Seyfi

2017-08-01

The relationship between sleep bruxism (SB) and selective serotonin reuptake inhibitors (SSRIs) is still under debate because of the lack of well-designed objective studies. The current study investigates possible effects of SSRIs, fluoxetine, and paroxetine on SB in patients with anxiety and depression. Thirty users of SSRIs for treatment of depression or anxiety were enrolled in the study. After clinical and anamnestic examination, 15 fluoxetine and 15 paroxetine users were included. For an objective evaluation of SB, a single-use disposable home screening device, BiteStrip, was used prior to the first SSRI intake and was repeated on the 7th and 15th days. Patients' self-reported data also were obtained for assessment of patient awareness. BiteStrip scores were significantly higher on the 7th and 15th days than the first measurement (p<0.01). There was an increase in 26 (86.6%) patients' bruxism scores on the 7th day. There was also an increase in 27 (90%) patients' bruxism scores on the 15th day. But according to patients' self-reports, only 6 patients had an awareness that bruxism symptoms were initiated or exacerbated 15days after starting fluoxetine or paroxetine. Fluoxetine and paroxetine, SSRIs used for the treatment of anxiety and depression, may initiate or aggravate SB. Clinicians should consider that SSRIs may be the cause of SB when SSRI users are referred to dental clinics for SB symptoms. As there is a shortage of researches on this subject, further studies are necessary to confirm the existence of SSRI-induced SB. Copyright © 2016. Published by Elsevier Ltd.

Fluoxetine prevents the development of depressive-like behavior in a mouse model of cancer related fatigue.

PubMed

Norden, Diana M; Devine, Raymond; Bicer, Sabahattin; Jing, Runfeng; Reiser, Peter J; Wold, Loren E; Godbout, Jonathan P; McCarthy, Donna O

2015-03-01

Cancer patients frequently suffer from fatigue, a complex syndrome associated with tiredness and depressed mood. Cancer-related fatigue (CRF) can be present at the time of diagnosis, escalates during treatment, and can persist for years after treatment. CRF negatively influences quality of life, limits functional independence, and is associated with decreased survival in patients with incurable disease. We have previously shown that increased pro-inflammatory cytokine expression in the brain contributes to depressive- and fatigue-like behaviors in a mouse model of CRF. Inflammatory cytokines increase the activity of indoleamine 2,3-dioxygenase (IDO) and kynurenine 3-monooxygenase (KMO), which competitively reduce serotonin synthesis. Reduced serotonin availability in the brain and increased production of alternative neuroactive metabolites of tryptophan are thought to contribute to the development of depression and fatigue. The purpose of this study was to determine the effects of fluoxetine, a selective serotonin reuptake inhibitor (SSRI), on brain cytokines and behavioral measures of fatigue and depression in tumor-bearing mice. Here we show that tumor growth increased brain expression of pro-inflammatory cytokines and KMO. Treatment with fluoxetine had no effect on tumor growth, muscle wasting, fatigue behavior, or cytokine expression in the brain. Fluoxetine, however, reduced depressive-like behaviors in tumor bearing mice. In conclusion, our data confirm that increased brain expression of pro-inflammatory cytokines is associated with tumor-induced fatigue- and depressive-like behaviors. However, it is possible to separate the effects of tumor growth on mood and fatigue-like behaviors using SSRIs such as fluoxetine. Copyright © 2014 Elsevier Inc. All rights reserved.
Disruption of social approach by MK-801, amphetamine, and fluoxetine in adolescent C57BL/6J mice.

PubMed

Moy, Sheryl S; Nonneman, Randal J; Shafer, Geoffrey O; Nikolova, Viktoriya D; Riddick, Natallia V; Agster, Kara L; Baker, Lorinda K; Knapp, Darin J

2013-01-01

Autism is a severe neurodevelopmental disorder, diagnosed on the basis of core behavioral symptoms. Although the mechanistic basis for the disorder is not yet known, genetic analyses have suggested a role for abnormal excitatory/inhibitory signaling systems in brain, including dysregulation of glutamatergic neurotransmission. In mice, the constitutive knockdown of NMDA receptors leads to social deficits, repetitive behavior, and self-injurious responses that reflect aspects of the autism clinical profile. However, social phenotypes differ with age: mice with reduced NMDA-receptor function exhibit hypersociability in adolescence, but markedly deficient sociability in adulthood. The present studies determined whether acute disruption of NMDA neurotransmission leads to exaggerated social approach, similar to that observed with constitutive disruption, in adolescent C57BL/6J mice. The effects of MK-801, an NMDA receptor antagonist, were compared with amphetamine, a dopamine agonist, and fluoxetine, a selective serotonin reuptake inhibitor, on performance in a three-chamber choice task. Results showed that acute treatment with MK-801 led to social approach deficits at doses without effects on entry numbers. Amphetamine also decreased social preference, but increased number of entries at every dose. Fluoxetine (10 mg/kg) had selective effects on social novelty preference. Withdrawal from a chronic ethanol regimen decreased activity, but did not attenuate sociability. Low doses of MK-801 and amphetamine were also evaluated in a marble-burying assay for repetitive behavior. MK-801, at a dose that did not disrupt sociability or alter entries, led to a profound reduction in marble-burying. Overall, these findings demonstrate that moderate alteration of NMDA, dopamine, or serotonin function can attenuate social preference in wild type mice. Copyright © 2012 Elsevier Inc. All rights reserved.
Disruption of social approach by MK-801, amphetamine, and fluoxetine in adolescent C57BL/6J mice

PubMed Central

Moy, Sheryl S.; Nonneman, Randal J.; Shafer, Geoffrey O.; Nikolova, Viktoriya D.; Riddick, Natallia V.; Agster, Kara L.; Baker, Lorinda K.; Knapp, Darin J.

2012-01-01

Autism is a severe neurodevelopmental disorder, diagnosed on the basis of core behavioral symptoms. Although the mechanistic basis for the disorder is not yet known, genetic analyses have suggested a role for abnormal excitatory/inhibitory signaling systems in brain, including dysregulation of glutamatergic neurotransmission. In mice, the constitutive knockdown of NMDA receptors leads to social deficits, repetitive behavior, and self-injurious responses that reflect aspects of the autism clinical profile. However, social phenotypes differ with age: mice with reduced NMDA-receptor function exhibit hypersociability in adolescence, but markedly deficient sociability in adulthood. The present studies determined whether acute disruption of NMDA neurotransmission leads to exaggerated social approach, similar to that observed with constitutive disruption, in adolescent C57BL/6J mice. The effects of MK-801, an NMDA receptor antagonist, were compared with amphetamine, a dopamine agonist, and fluoxetine, a selective serotonin reuptake inhibitor, on performance in a three-chamber choice task. Results showed that acute treatment with MK-801 led to social approach deficits at doses without effects on entry numbers. Amphetamine also decreased social preference, but increased number of entries at every dose. Fluoxetine (10 mg/kg) had selective effects on social novelty preference. Withdrawal from a chronic ethanol regimen decreased activity, but did not attenuate sociability. Low doses of MK-801 and amphetamine were also evaluated in a marble-burying assay for repetitive behavior. MK-801, at a dose that did not disrupt sociability or alter entries, led to a profound reduction in marble-burying. Overall, these findings demonstrate that moderate alteration of NMDA, dopamine, or serotonin function can attenuate social preference in wild type mice. PMID:22898204
The expression of HoxB5 and SPC in neonatal rat lung after exposure to fluoxetine.

PubMed

Taghizadeh, Razieh; Taghipour, Zahra; Karimi, Akbar; Shamsizadeh, Ali; Taghavi, Mohammad Mohsen; Shariati, Mahdi; Shabanizadeh, Ahmad; Jafari Naveh, Hamid Reza; Bidaki, Reza; Aminzadeh, Fariba

2016-01-01

Approximately 10% of pregnant women suffer from pregnancy-associated depression. Fluoxetine, as a selective serotonin reuptake inhibitor, is being employed as a therapy for depressive disorders. The present study aimed to determine the effects of fluoxetine on neonatal lung development. Thirty pregnant Wistar rats (weighing 200-250 g) were treated daily with 7 mg/kg fluoxetine from gestation day 0 to gestation day 21, via gavage. The control group received a similar volume of distilled water only. Following delivery, the newborns and their lungs were immediately weighed in both of the groups. The right lung was fixed for histological assessments while the left lung was used for evaluation of the expression of SPC and HoxB5 by the real-time polymerase chain reaction method. Results have indicated that even though the body weight and the number of neonatal rats in both groups were the same, the lung weight of neonates exposed to fluoxetine was significantly different compared to the control group ( P <0.05). Expression of both genes was increased, nonetheless, only elevation of HoxB5 was significant ( P <0.05). Histological studies demonstrated that lung tissue in the fluoxetine treatment group morphologically appears to be similar to the pseudoglandular phase, whereas the control group lungs experienced more development. According to the upregulated expression of HoxB5 concerning histological findings, results of the present study showed that fluoxetine can influence lung growth and may in turn lead to delay in lung development. So establishment of studies to identify the effects of antidepressant drugs during pregnancy is deserved.
ECT Has Greater Efficacy Than Fluoxetine in Alleviating the Burden of Illness for Patients with Major Depressive Disorder: A Taiwanese Pooled Analysis.

PubMed

Lin, Ching-Hua; Huang, Chun-Jen; Chen, Cheng-Chung

2018-01-01

The burden of major depressive disorder includes suffering due to symptom severity, functional impairment, and quality of life deficits. The aim of this study was to compare the differences between electroconvulsive therapy and pharmacotherapy in reducing such burdens. This was a pooled analysis study including 2 open-label trials for major depressive disorder inpatients receiving either standard bitemporal and modified electroconvulsive therapy with a maximum of 12 sessions or 20 mg/d of fluoxetine for 6 weeks. Symptom severity, functioning, and quality of life were assessed using the 17-item Hamilton Rating Scale for Depression, the Modified Work and Social Adjustment Scale, and SF-36. Side effects following treatment, including subjective memory impairment, nausea/vomiting, and headache, were recorded. The differences between these 2 groups in 17-item Hamilton Rating Scale for Depression, Modified Work and Social Adjustment Scale, quality of life, side effects, and time to response (at least a 50% reduction of 17-item Hamilton Rating Scale for Depression) and remission (17-item Hamilton Rating Scale for Depression ≤7) following treatment were analyzed. Electroconvulsive therapy (n=116) showed a significantly greater reduction in 17-item Hamilton Rating Scale for Depression, Modified Work and Social Adjustment Scale, and quality of life deficits and had significantly shorter time to response/remission than fluoxetine (n=126). However, the electroconvulsive therapy group was more likely to experience subjective memory impairment and headache. Compared with fluoxetine, electroconvulsive therapy was more effective in alleviating the burden of major depressive disorder and had a substantially increased speed of response/remission in the acute phase. Increased education and information about electroconvulsive therapy for clinicians, patients, and their families and the general public is warranted. © The Author(s) 2017. Published by Oxford University Press on behalf
ECT Has Greater Efficacy Than Fluoxetine in Alleviating the Burden of Illness for Patients with Major Depressive Disorder: A Taiwanese Pooled Analysis

PubMed Central

Huang, Chun-Jen; Chen, Cheng-Chung

2018-01-01

Abstract Background The burden of major depressive disorder includes suffering due to symptom severity, functional impairment, and quality of life deficits. The aim of this study was to compare the differences between electroconvulsive therapy and pharmacotherapy in reducing such burdens. Methods This was a pooled analysis study including 2 open-label trials for major depressive disorder inpatients receiving either standard bitemporal and modified electroconvulsive therapy with a maximum of 12 sessions or 20 mg/d of fluoxetine for 6 weeks. Symptom severity, functioning, and quality of life were assessed using the 17-item Hamilton Rating Scale for Depression, the Modified Work and Social Adjustment Scale, and SF-36. Side effects following treatment, including subjective memory impairment, nausea/vomiting, and headache, were recorded. The differences between these 2 groups in 17-item Hamilton Rating Scale for Depression, Modified Work and Social Adjustment Scale, quality of life, side effects, and time to response (at least a 50% reduction of 17-item Hamilton Rating Scale for Depression) and remission (17-item Hamilton Rating Scale for Depression ≤7) following treatment were analyzed. Results Electroconvulsive therapy (n=116) showed a significantly greater reduction in 17-item Hamilton Rating Scale for Depression, Modified Work and Social Adjustment Scale, and quality of life deficits and had significantly shorter time to response/remission than fluoxetine (n=126). However, the electroconvulsive therapy group was more likely to experience subjective memory impairment and headache. Conclusions Compared with fluoxetine, electroconvulsive therapy was more effective in alleviating the burden of major depressive disorder and had a substantially increased speed of response/remission in the acute phase. Increased education and information about electroconvulsive therapy for clinicians, patients, and their families and the general public is warranted. PMID:29228200
Potentiation of omega-3 fatty acid antidepressant-like effects with low non-antidepressant doses of fluoxetine and mirtazapine.

PubMed

Laino, Carlos Horacio; Fonseca, Cristina; Sterin-Speziale, Norma; Slobodianik, Nora; Reinés, Analía

2010-12-01

Despite the advances in psychopharmacology, the treatment of depressive disorders is still not satisfactory. Side effects and resistance to antidepressant drugs are the greatest complications during treatment. Based on recent evidence, omega-3 fatty acids may influence vulnerability and outcome in depressive disorders. The aim of this study was to further characterize the omega-3 antidepressant-like effect in rats in terms of its behavioral features in the depression model forced swimming test either alone or in combination with antidepressants fluoxetine or mirtazapine. Ultimately, we prompted to determine the lowest dose at which omega-3 fatty acids and antidepressant drugs may still represent a pharmacological advantage when employed in combined treatments. Chronic diet supplementation with omega-3 fatty acids produced concentration-dependent antidepressant-like effects in the forced swimming test displaying a behavioral profile similar to fluoxetine but different from mirtazapine. Fluoxetine or mirtazapine at antidepressant doses (10 and 20 mg/kg/day, respectively) rendered additive effects in combination with omega-3 fatty acid supplementation (720 mg/kg/day). Beneficial effects of combined treatment were also observed at sub-effective doses (1 mg/kg/day) of fluoxetine or mirtazapine, since in combination with omega-3 fatty acids (720 mg/kg/day), antidepressants potentiated omega-3 antidepressant-like effects. The antidepressant-like effects occurred in the absence of changes in brain phospholipid classes. The therapeutic approach of combining omega-3 fatty acids with low ineffective doses of antidepressants might represent benefits in the treatment of depression, especially in patients with depression resistant to conventional treatments and even may contribute to patient compliance by decreasing the magnitude of some antidepressant dose-dependent side effects. Copyright © 2010 Elsevier B.V. All rights reserved.
Antidepressant effects of acupoint stimulation and fluoxetine by increasing dendritic arborization and spine density in CA1 hippocampal neurons of socially isolated rats.

PubMed

Dávila-Hernández, Amalia; Zamudio, Sergio R; Martínez-Mota, Lucía; González-González, Roberto; Ramírez-San Juan, Eduardo

2018-05-14

Given the importance of depression and the adverse effects of conventional treatment, it is necessary to seek complementary therapies. In a rat model of depression, this study aimed to assess the behavioral and morphological effects of embedding absorbable thread in acupoints (acu-catgut), and compare the results to those of fluoxetine treatment and the corresponding control groups. Therefore, depressive-like behavior was evaluated with the forced swimming test, and dendritic morphology (in the CA1 hippocampal region) with the Golgi-Cox technique and Sholl analysis. After weaning, male Sprague-Dawley rats were housed in social isolation for 8 weeks to induce depressive-like behavior. They were then given a 21-day treatment by stimulating acupoints with acu-catgut (AC) or fluoxetine (FX) (2 mg/kg). Rats were divided into six groups: Control (socially housed), social isolation (SI), SI + AC, SI + Sham (sham embedding of thread), SI + FX and SI + VH (vehicle). Compared to fluoxetine, acu-catgut treatment was more effective in reversing depressive-like behavior elicited by SI. The SI-induced reduction in dendritic length and spine density in hippocampal CA1 pyramidal neurons was attenuated after prolonged treatment with acu-catgut or fluoxetine. Hence, both treatments proved capable of reversing depressive-like alterations caused by SI, likely due to dendritic remodeling in the hippocampus. Copyright © 2018 Elsevier B.V. All rights reserved.
An Exploratory Analysis of the Impact of Family Functioning on Treatment for Depression in Adolescents

ERIC Educational Resources Information Center

Feeny, Norah C.; Silva, Susan G.; Reinecke, Mark A.; McNulty, Steven; Findling, Robert L.; Rohde, Paul; Curry, John F.; Ginsburg, Golda S.; Kratochvil, Christopher J.; Pathak, Sanjeev M.; May, Diane E.; Kennard, Betsy D.; Simons, Anne D.; Wells, Karen C.; Robins, Michele; Rosenberg, David; March, John S.

2009-01-01

This article explores aspects of family environment and parent-child conflict that may predict or moderate response to acute treatments among depressed adolescents (N = 439) randomly assigned to fluoxetine, cognitive behavioral therapy, their combination, or placebo. Outcomes were Week 12 scores on measures of depression and global impairment. Of…
Genetic background contributes to the co-morbidity of anxiety and depression with audiogenic seizure propensity and responses to fluoxetine treatment.

PubMed

Sarkisova, Karine Yu; Fedotova, Irina B; Surina, Natalia M; Nikolaev, Georgy M; Perepelkina, Olga V; Kostina, Zoya A; Poletaeva, Inga I

2017-03-01

Anxiety and depression are the most frequent comorbidities of different types of convulsive and non-convulsive epilepsies. Increased anxiety and depression-like phenotype have been described in the genetic absence epilepsy models as well as in models of limbic epilepsy and acquired seizure models, suggesting a neurobiological connection. However, whether anxiety and/or depression are comorbid to audiogenic epilepsy remains unclear. The aim of this study was to investigate whether anxiety or depression-like behavior can be found in rat strains with different susceptibility to audiogenic seizures (AS) and whether chronic fluoxetine treatment affects this co-morbidity. Behavior in the elevated plus-maze and the forced swimming test was studied in four strains: Wistar rats non-susceptible to AS; Krushinsky-Molodkina (KM) strain, selectively bred for AS propensity from outbred Wistar rats; and a selection lines bred for maximal AS expression (strain "4") and for a lack of AS (strain "0") from KM×Wistar F2 hybrids. Effects of chronic antidepressant treatment on AS and behavior were also evaluated. Anxiety and depression levels were higher in KM rats (with AS) compared with Wistar rats (without AS), indicating the comorbidity with AS. However, in strains "4" and "0" with contrasting AS expression, but with a genetic background close to KM rats, anxiety and depression were not as divergent as in KMs versus Wistars. Fluoxetine treatment exerted an antidepressant effect in all rat strains irrespective of its effect on AS. Genetic background contributes substantively to the co-morbidity of anxiety and depression with AS propensity. Copyright © 2016 Elsevier Inc. All rights reserved.
Mouse Strain Affects Behavioral and Neuroendocrine Stress Responses Following Administration of Probiotic Lactobacillus rhamnosus JB-1 or Traditional Antidepressant Fluoxetine.

PubMed

McVey Neufeld, Karen-Anne; Kay, Sebastian; Bienenstock, John

2018-01-01

Currently, there is keen interest in the development of alternative therapies in the treatment of depression. Given the explosion of research focused on the microbiota-gut-brain axis, consideration has turned to the potential of certain probiotics to improve patient outcomes for those suffering from mood disorders. Here we examine the abilities of a known antidepressant, fluoxetine, and the probiotic Lactobacillus rhamnosus JB-1™, to attenuate responses to two established criteria for depressive-like behavior in animal models, the tail suspension test (TST) and the corticosterone response to an acute restraint stressor. We examine two different strains of mice known to differ in the extent to which they express both anxiety-like behavior and measures of despair-BALB/c and Swiss Webster-with respectively high and normal behavioral phenotypes for each. While adult male BALB/c mice responded with increased antidepressive-like behavior to both fluoxetine and L. rhamnosus JB-1 in both the TST and the corticosterone stress response, SW mice did not respond to either treatment as compared to controls. These findings highlight the importance of investigating putative antidepressants in mouse strains known to express face validity for some markers of depression. Clinical studies examining the activity of L. rhamnosus JB-1 in patients suffering from mood disorders are warranted, as well as further pre-clinical work examining how interactions between host genotype and intestinal microbial alterations may impact behavioral responses. This study adds to the literature supporting the possibility that modifying the intestinal microbiota via probiotics represents a promising potential therapeutic breakthrough in the treatment of psychiatric disease.
Mouse Strain Affects Behavioral and Neuroendocrine Stress Responses Following Administration of Probiotic Lactobacillus rhamnosus JB-1 or Traditional Antidepressant Fluoxetine

PubMed Central

McVey Neufeld, Karen-Anne; Kay, Sebastian; Bienenstock, John

2018-01-01

Currently, there is keen interest in the development of alternative therapies in the treatment of depression. Given the explosion of research focused on the microbiota-gut-brain axis, consideration has turned to the potential of certain probiotics to improve patient outcomes for those suffering from mood disorders. Here we examine the abilities of a known antidepressant, fluoxetine, and the probiotic Lactobacillus rhamnosus JB-1™, to attenuate responses to two established criteria for depressive-like behavior in animal models, the tail suspension test (TST) and the corticosterone response to an acute restraint stressor. We examine two different strains of mice known to differ in the extent to which they express both anxiety-like behavior and measures of despair—BALB/c and Swiss Webster—with respectively high and normal behavioral phenotypes for each. While adult male BALB/c mice responded with increased antidepressive-like behavior to both fluoxetine and L. rhamnosus JB-1 in both the TST and the corticosterone stress response, SW mice did not respond to either treatment as compared to controls. These findings highlight the importance of investigating putative antidepressants in mouse strains known to express face validity for some markers of depression. Clinical studies examining the activity of L. rhamnosus JB-1 in patients suffering from mood disorders are warranted, as well as further pre-clinical work examining how interactions between host genotype and intestinal microbial alterations may impact behavioral responses. This study adds to the literature supporting the possibility that modifying the intestinal microbiota via probiotics represents a promising potential therapeutic breakthrough in the treatment of psychiatric disease.
Depression-like behavior and mechanical allodynia are reduced by bis selenide treatment in mice with chronic constriction injury: a comparison with fluoxetine, amitriptyline, and bupropion.

PubMed

Jesse, Cristiano R; Wilhelm, Ethel A; Nogueira, Cristina W

2010-12-01

Neuropathic pain is associated with significant co-morbidities, including depression, which impact considerably on the overall patient experience. Pain co-morbidity symptoms are rarely assessed in animal models of neuropathic pain. Neuropathic pain is characterized by hyperexcitability within nociceptive pathways and remains difficult to treat with standard analgesics. The present study determined the effect of bis selenide and conventional antidepressants (fluoxetine, amitriptyline, and bupropion) on neuropathic pain using mechanical allodynic and on depressive-like behavior. Male mice were subjected to chronic constriction injury (CCI) or sham surgery and were assessed on day 14 after operation. Mice received oral treatment with bis selenide (1-5 mg/kg), fluoxetine, amitriptyline, or bupropion (10-30 mg/kg). The response frequency to mechanical allodynia in mice was measured with von Frey hairs. Mice were evaluated in the forced swimming test (FST) test for depression-like behavior. The CCI procedure produced mechanical allodynia and increased depressive-like behavior in the FST. All of the drugs produced antiallodynic effects in CCI mice and produced antidepressant effects in control mice without altering locomotor activity. In CCI animals, however, only the amitriptyline and bis selenide treatments significantly reduced immobility in the FST. These data demonstrate an important dissociation between the antiallodynic and antidepressant effects in mice when tested in a model of neuropathic pain. Depressive behavior in CCI mice was reversed by bis selenide and amitriptyline but not by the conventional antidepressants fluoxetine and buproprion. Bis selenide was more potent than the other drugs tested for antidepressant-like and antiallodynic effects in mice.
Antidepressant behavioral effects of duloxetine and fluoxetine in the rat forced swimming test.

PubMed

Ciulla, Leandro; Menezes, Honório Sampaio; Bueno, Bárbara Beatriz Moreira; Schuh, Alexandre; Alves, Rafael José Vargas; Abegg, Milena Pacheco

2007-01-01

To compare the effects of the antidepressant drugs duloxetine and fluoxetine on depressive behaviors in rodents. Eighteen male Wistar rats were given systemic injections of duloxetine, fluoxetine, or saline prior to a Forced Swimming Test (FST). Immobility and number of stops were measured. Rats given injections of fluoxetine displayed significantly less immobility (p = 0.02) and fewer stops than the control group (p = 0.003). Duloxetine significantly reduced the number of stops (p = 0.003), but did not effect immobility (p = 0.48). Duloxetine and fluoxetine reduced depressive behaviors in the Forced FST. However, our findings suggest that fluoxetine is more effective than duloxetine.
Alterations in amino acid levels in mouse brain regions after adjunctive treatment of brexpiprazole with fluoxetine: comparison with (R)-ketamine.

PubMed

Ma, Min; Ren, Qian; Fujita, Yuko; Yang, Chun; Dong, Chao; Ohgi, Yuta; Futamura, Takashi; Hashimoto, Kenji

2017-11-01

Brexpiprazole, a serotonin-dopamine activity modulator, is approved in the USA as an adjunctive therapy to antidepressants for treating major depressive disorders. Similar to the N-methyl-D-aspartate receptor (NMDAR) antagonist ketamine, the combination of brexpiprazole and fluoxetine has demonstrated antidepressant-like effects in animal models of depression. The present study was conducted to examine whether the combination of brexpiprazole and fluoxetine could affect the tissue levels of amino acids [glutamate, glutamine, γ-aminobutyric acid (GABA), D-serine, L-serine, and glycine] that are associated with NMDAR neurotransmission. The tissue levels of amino acids in the frontal cortex, striatum, hippocampus, and cerebellum were measured after a single [or repeated (14 days)] oral administration of vehicle, fluoxetine (10 mg/kg), brexpiprazole (0.1 mg/kg), or a combination of the two drugs. Furthermore, we measured the tissue levels of amino acids after a single administration of the NMDAR antagonist (R)-ketamine. A single injection of the combination of fluoxetine and brexpiprazole significantly increased GABA levels in the striatum, the D-serine/L-serine ratio in the frontal cortex, and the glycine/L-serine ratio in the hippocampus. A repeated administration of the combination significantly altered the tissue levels of amino acids in all regions. Interestingly, a repeated administration of the combination significantly decreased the D-serine/L-serine ratio in the frontal cortex, striatum, and hippocampus. In contrast, a single administration of (R)-ketamine significantly increased the D-serine/L-serine ratio in the frontal cortex. These results suggested that alterations in the tissue levels of these amino acids may be involved in the antidepressant-like effects of the combination of brexpiprazole and fluoxetine.
Uptake, accumulation and metabolization of the antidepressant fluoxetine by Mytilus galloprovincialis.

PubMed

Silva, Liliana J G; Martins, Margarida C; Pereira, André M P T; Meisel, Leonor M; Gonzalez-Rey, Maria; Bebianno, Maria João; Lino, Celeste M; Pena, Angelina

2016-06-01

Fluoxetine, a selective serotonin re-uptake inhibitor (SSRI) antidepressant, is among the most prescribed pharmaceutical active substances worldwide. This study aimed to assess its accumulation and metabolization in the mussel Mytillus galloprovincialis, considered an excellent sentinel species for traditional and emerging pollutants. Mussels were collected from Ria Formosa Lagoon, Portugal, and exposed to a nominal concentration of fluoxetine (75 ng L(-1)) for 15 days. Approximately 1 g of whole mussel soft tissues was extracted with acetonitrile:formic acid, loaded into an Oasis MCX cartridge, and fluoxetine analysed by liquid chromatography with tandem mass spectrometry (LC-MSn). After 3 days of exposure, fluoxetine was accumulated in 70% of the samples, with a mean of 2.53 ng g(-1) dry weight (d.w.) and norfluoxetine was only detected in one sample (10%), at 3.06 ng g(-1) d.w. After 7 days of exposure, the accumulation of fluoxetine and norfluoxetine increased up to 80 and 50% respectively, and their mean accumulated levels in mussel tissues were up to 4.43 and 2.85 ng g(-1) d.w., respectively. By the end of the exposure period (15 days), both compounds were detected in 100% of the samples (mean of 9.31 and 11.65 ng g(-1) d.w., respectively). Statistical analysis revealed significant accumulation differences between the 3rd and 15th day of exposure for fluoxetine, and between the 3rd and 7th against the 15th day of exposure for norfluoxetine. These results suggest that the fluoxetine accumulated in mussel tissues is likely to be metabolised into norfluoxetine with the increase of the time of exposure, giving evidence that at these realistic environmental concentrations, toxic effects of fluoxetine in mussel tissues may occur. Copyright © 2016 Elsevier Ltd. All rights reserved.
Effect of fluoxetine on induced tooth movement in rats.

PubMed

Franzon Frigotto, Giovana Carla; Miranda de Araujo, Cristiano; Guariza Filho, Odilon; Tanaka, Orlando Motohiro; Batista Rodrigues Johann, Aline Cristina; Camargoa, Elisa Souza

2015-09-01

Fluoxetine is a widely used antidepressant. Its various effects on bone mineral density are well described. The aim of this study was to evaluate the effect of fluoxetine on induced tooth movement. Seventy-two Wistar rats were divided into 3 groups: M (n = 24; 0.9% saline solution and induced tooth movement), FM (n = 24; fluoxetine, 10 mg/kg, and induced tooth movement), and F (n = 24; fluoxetine, 10 mg/kg only). After 30 days of daily saline solution or fluoxetine administration, an orthodontic appliance (30 cN) was used to displace the first molar mesially in groups M and FM. The animals were killed 3, 7, and 14 days after placement of the orthodontic appliances. The animals in group F did not receive induced tooth movement but were killed at the same times. We evaluated tooth movement rates, collagen neoformation rates by polarization microscopy, numbers of osteoclast by tartrate-resistant acid phosphatase, and trabecular bone modeling by microcomputed tomography of the femur. The tooth movement rates were similar in groups M and FM at all studied time points (P >0.05). The rate of newly formed collagen had a reverse pattern in groups M and FM, but the difference was not statistically significant (P >0.05). There were significantly more osteoclasts in group FM than in group F on day 3 (P <0.01). The trabecular spacing was significantly larger in group F compared with group M on day 14 (P <0.05). Fluoxetine did not interfere with induced tooth movement or trabecular bone in rats. Copyright © 2015 American Association of Orthodontists. Published by Elsevier Inc. All rights reserved.
Fluoxetine induces input-specific hippocampal dendritic spine remodeling along the septotemporal axis in adulthood and middle age.

PubMed

McAvoy, Kathleen; Russo, Craig; Kim, Shannen; Rankin, Genelle; Sahay, Amar

2015-11-01

Fluoxetine, a selective serotonin-reuptake inhibitor (SSRI), is known to induce structural rearrangements and changes in synaptic transmission in hippocampal circuitry. In the adult hippocampus, structural changes include neurogenesis, dendritic, and axonal plasticity of pyramidal and dentate granule neurons, and dedifferentiation of dentate granule neurons. However, much less is known about how chronic fluoxetine affects these processes along the septotemporal axis and during the aging process. Importantly, studies documenting the effects of fluoxetine on density and distribution of spines along different dendritic segments of dentate granule neurons and CA1 pyramidal neurons along the septotemporal axis of hippocampus in adulthood and during aging are conspicuously absent. Here, we use a transgenic mouse line in which mature dentate granule neurons and CA1 pyramidal neurons are genetically labeled with green fluorescent protein (GFP) to investigate the effects of chronic fluoxetine treatment (18 mg/kg/day) on input-specific spine remodeling and mossy fiber structural plasticity in the dorsal and ventral hippocampus in adulthood and middle age. In addition, we examine levels of adult hippocampal neurogenesis, maturation state of dentate granule neurons, neuronal activity, and glutamic acid decarboxylase-67 expression in response to chronic fluoxetine in adulthood and middle age. Our studies reveal that while chronic fluoxetine fails to augment adult hippocampal neurogenesis in middle age, the middle-aged hippocampus retains high sensitivity to changes in the dentate gyrus (DG) such as dematuration, hypoactivation, and increased glutamic acid decarboxylase 67 (GAD67) expression. Interestingly, the middle-aged hippocampus shows greater sensitivity to fluoxetine-induced input-specific synaptic remodeling than the hippocampus in adulthood with the stratum-oriens of CA1 exhibiting heightened structural plasticity. The input-specific changes and circuit
Convergence of glycogen synthase kinase 3β and GR signaling in response to fluoxetine treatment in chronically stressed female and male rats.

PubMed

Mitic, Milos; Brkic, Zeljka; Lukic, Iva; Adzic, Miroslav

2017-08-30

Accumulating evidence strongly suggest that impaired glucocorticoid receptor (GR) signaling is involved in stress-related mood disorders, and nominate GR as a potential target for antidepressants (ADs). It is known that different classes of ADs affects the GR action via modifying its phosphorylation, while the mechanism through which ADs alter GR phosphorylation targeted by GSK3β, a kinase modulated via serotonin neurotransmission, are unclear. On this basis, we investigated whether GSK3β-GR signaling could be a convergence point of fluoxetine action on brain function and behavior, by examining its effect on GSK3β targeted-GR phosphorylation on threonine 171 (pGR171), and expression of GR-regulated genes in the hippocampus of female and male rats exposed to chronic isolation stress. Stress induced sex-specific GSK3β-targeted phosphorylation of pGR171 in the nucleus of the hippocampus of stressed animals. Namely, while in females stress triggered coupled action of GSK3β-pGR171 signaling, in males changes in pGR171 levels did not correspond to GSK3β activity. On the other hand, fluoxetine managed to up-regulate this pathway in sex-unbiased manner. Furthermore, fluoxetine reverted stress-induced changes in most of the analyzed genes in males, CRH, 5-HT1a and p11, while in females its effect was limited to CRH. These data further suggest that pGR171 signaling affects cellular localization of GR in response to chronic stress and fluoxetine in both sexes. Collectively, our results describe a novel convergence point between GR signaling and GSK3β pathway in rat hippocampus in response to stress and fluoxetine in both sexes and its involvement in fluoxetine-regulated brain function in males. Copyright © 2017 Elsevier B.V. All rights reserved.
Acute Time to Response in the Treatment for Adolescents with Depression Study (TADS)

ERIC Educational Resources Information Center

Kratochvil, Christopher; Emslie, Graham; Silva, Susan; McNulty, Steve; Walkup, John; Curry, John; Reinecke, Mark; Vitiello, Benedetto; Rohde, Paul; Feeny, Nora; Casat, Charles; Pathak, Sanjeev; Weller, Elizabeth; May, Diane; Mayes, Taryn; Robins, Michele; March, John

2006-01-01

Objective: To examine the time to response for both pharmacotherapy and psychotherapy in the Treatment for Adolescents with Depression Study (TADS). Method: Adolescents (N = 439, ages 12 to 17 years) with major depressive disorder were randomized to fluoxetine (FLX), cognitive-behavioral therapy (CBT), their combination (COMB), or pill placebo…

Fluoxetine Does Not Enhance Visual Perceptual Learning and Triazolam Specifically Impairs Learning Transfer

PubMed Central

Lagas, Alice K.; Black, Joanna M.; Byblow, Winston D.; Fleming, Melanie K.; Goodman, Lucy K.; Kydd, Robert R.; Russell, Bruce R.; Stinear, Cathy M.; Thompson, Benjamin

2016-01-01

The selective serotonin reuptake inhibitor fluoxetine significantly enhances adult visual cortex plasticity within the rat. This effect is related to decreased gamma-aminobutyric acid (GABA) mediated inhibition and identifies fluoxetine as a potential agent for enhancing plasticity in the adult human brain. We tested the hypothesis that fluoxetine would enhance visual perceptual learning of a motion direction discrimination (MDD) task in humans. We also investigated (1) the effect of fluoxetine on visual and motor cortex excitability and (2) the impact of increased GABA mediated inhibition following a single dose of triazolam on post-training MDD task performance. Within a double blind, placebo controlled design, 20 healthy adult participants completed a 19-day course of fluoxetine (n = 10, 20 mg per day) or placebo (n = 10). Participants were trained on the MDD task over the final 5 days of fluoxetine administration. Accuracy for the trained MDD stimulus and an untrained MDD stimulus configuration was assessed before and after training, after triazolam and 1 week after triazolam. Motor and visual cortex excitability were measured using transcranial magnetic stimulation. Fluoxetine did not enhance the magnitude or rate of perceptual learning and full transfer of learning to the untrained stimulus was observed for both groups. After training was complete, trazolam had no effect on trained task performance but significantly impaired untrained task performance. No consistent effects of fluoxetine on cortical excitability were observed. The results do not support the hypothesis that fluoxetine can enhance learning in humans. However, the specific effect of triazolam on MDD task performance for the untrained stimulus suggests that learning and learning transfer rely on dissociable neural mechanisms. PMID:27807412
Effects of fluoxetine on the rat brain in the forced swimming test: a [F-18]FDG micro-PET imaging study.

PubMed

Jang, Dong-Pyo; Lee, So-Hee; Park, Chan-Woong; Lee, Sang-Yoon; Kim, Young-Bo; Cho, Zang-Hee

2009-02-13

We used the [F-18]FDG micro-PET neuroimaging to examine the effects of fluoxetine on brain activity in rats and on their behavioral response in the forced swimming test (FST). In the first experiment, the rats were administered doses of fluoxetine (10 or 20mg/kg) 24, 19 and 1h before the rat brains were scanned. Fluoxetine induced strong activation of the dorsal hippocampus and the deactivation of the inferior colliculus, medulla oblongata, and prelimbic cortex in a dose-dependent manner. These results seemed to be related with the changes in 5-HT (5-hydroxytryptamine, serotonin) levels after selective serotonin reuptake-inhibitor treatments. In the second experiment, the changes in glucose metabolism in the test session were measured after fluoxetine was given between pre-test and test sessions of the FST. Fluoxetine administration significantly decreased immobility behavior compared with saline administration. At the same time, the activity of the insular/piriform cortex decreased significantly. In contrast, the extent of cerebellar activation increased. The glucose metabolism of the dorsal hippocampus also increased, which suggests that post-stress changes in the facilitation of hippocampal serotonergic neurotransmission lead to decreased immobilization in the FST.
Fluoxetine induces input-specific hippocampal dendritic spine remodeling along the septo-temporal axis in adulthood and middle age

PubMed Central

McAvoy, Kathleen; Russo, Craig; Kim, Shannen; Rankin, Genelle; Sahay, Amar

2015-01-01

Fluoxetine, a selective serotonin-reuptake inhibitor (SSRI), is known to induce structural rearrangements and changes in synaptic transmission in hippocampal circuitry. In the adult hippocampus, structural changes include neurogenesis, dendritic and axonal plasticity of pyramidal and dentate granule neurons, and dedifferentiation of dentate granule neurons. However, much less is known about how chronic fluoxetine affects these processes along the septo-temporal axis and during the aging process. Importantly, studies documenting the effects of fluoxetine on density and distribution of spines along different dendritic segments of dentate granule neurons and CA1 pyramidal neurons along the septo-temporal axis of hippocampus in adulthood and during aging are conspicuously absent. Here, we use a transgenic mouse line in which mature dentate granule neurons and CA1 pyramidal neurons are genetically labeled with green fluorescent protein (GFP) to investigate the effects of chronic fluoxetine treatment (18mg/kg/day) on input-specific spine remodeling and mossy fiber structural plasticity in the dorsal and ventral hippocampus in adulthood and middle age. In addition, we examine levels of adult hippocampal neurogenesis, maturation state of dentate granule neurons, neuronal activity and glutamic acid decarboxylase-67 expression in response to chronic fluoxetine in adulthood and middle age. Our studies reveal that while chronic fluoxetine fails to augment adult hippocampal neurogenesis in middle age, the middle-aged hippocampus retains high sensitivity to changes in the dentate gyrus (DG) such as dematuration, hypoactivation, and increased glutamic acid decarboxylase 67 (GAD67) expression. Interestingly, the middle-aged hippocampus shows greater sensitivity to fluoxetine-induced input-specific synaptic remodeling than the hippocampus in adulthood with the stratum-oriens of CA1 exhibiting heightened structural plasticity. The input-specific changes and circuit
Fluoxetine ameliorates cartilage degradation in osteoarthritis by inhibiting Wnt/β-catenin signaling.

PubMed

Miyamoto, Kentaro; Ohkawara, Bisei; Ito, Mikako; Masuda, Akio; Hirakawa, Akihiro; Sakai, Tadahiro; Hiraiwa, Hideki; Hamada, Takashi; Ishiguro, Naoki; Ohno, Kinji

2017-01-01

Abnormal activation of the Wnt/β-catenin signaling is implicated in the osteoarthritis (OA) pathology. We searched for a pre-approved drug that suppresses abnormally activated Wnt/β-catenin signaling and has a potency to reduce joint pathology in OA. We introduced the TOPFlash reporter plasmid into HCS-2/8 human chondrosarcoma cells to estimate the Wnt/β-catenin activity in the presence of 10 μM each compound in a panel of pre-approved drugs. We found that fluoxetine, an antidepressant in the class of selective serotonin reuptake inhibitors (SSRI), down-regulated Wnt/β-catenin signaling in human chondrosarcoma cells. Fluoxetine inhibited both Wnt3A- and LiCl-induced loss of proteoglycans in chondrogenically differentiated ATDC5 cells. Fluoxetine increased expression of Sox9 (the chondrogenic master regulator), and decreased expressions of Axin2 (a marker for Wnt/β-catenin signaling) and Mmp13 (matrix metalloproteinase 13). Fluoxetine suppressed a LiCl-induced increase of total β-catenin and a LiCl-induced decrease of phosphorylated β-catenin in a dose-dependent manner. An in vitro protein-binding assay showed that fluoxetine enhanced binding of β-catenin with Axin1, which is a scaffold protein forming the degradation complex for β-catenin. Fluoxetine suppressed LiCl-induced β-catenin accumulation in human OA chondrocytes. Intraarticular injection of fluoxetine in a rat OA model ameliorated OA progression and suppressed β-catenin accumulation.
Fluoxetine ameliorates cartilage degradation in osteoarthritis by inhibiting Wnt/β-catenin signaling

PubMed Central

Miyamoto, Kentaro; Ito, Mikako; Masuda, Akio; Hirakawa, Akihiro; Sakai, Tadahiro; Hiraiwa, Hideki; Hamada, Takashi; Ishiguro, Naoki; Ohno, Kinji

2017-01-01

Abnormal activation of the Wnt/β-catenin signaling is implicated in the osteoarthritis (OA) pathology. We searched for a pre-approved drug that suppresses abnormally activated Wnt/β-catenin signaling and has a potency to reduce joint pathology in OA. We introduced the TOPFlash reporter plasmid into HCS-2/8 human chondrosarcoma cells to estimate the Wnt/β-catenin activity in the presence of 10 μM each compound in a panel of pre-approved drugs. We found that fluoxetine, an antidepressant in the class of selective serotonin reuptake inhibitors (SSRI), down-regulated Wnt/β-catenin signaling in human chondrosarcoma cells. Fluoxetine inhibited both Wnt3A- and LiCl-induced loss of proteoglycans in chondrogenically differentiated ATDC5 cells. Fluoxetine increased expression of Sox9 (the chondrogenic master regulator), and decreased expressions of Axin2 (a marker for Wnt/β-catenin signaling) and Mmp13 (matrix metalloproteinase 13). Fluoxetine suppressed a LiCl-induced increase of total β-catenin and a LiCl-induced decrease of phosphorylated β-catenin in a dose-dependent manner. An in vitro protein-binding assay showed that fluoxetine enhanced binding of β-catenin with Axin1, which is a scaffold protein forming the degradation complex for β-catenin. Fluoxetine suppressed LiCl-induced β-catenin accumulation in human OA chondrocytes. Intraarticular injection of fluoxetine in a rat OA model ameliorated OA progression and suppressed β-catenin accumulation. PMID:28926590
Desvenlafaxine Versus Placebo in a Fluoxetine-Referenced Study of Children and Adolescents with Major Depressive Disorder

PubMed Central

Murphy, William; Abbas, Richat; Chiles, Deborah; England, Richard D.; Ramaker, Sara; Wajsbrot, Dalia B.

2018-01-01

Abstract Objectives: To evaluate the short-term efficacy and safety of desvenlafaxine (25–50 mg/d) compared with placebo in children and adolescents with major depressive disorder (MDD). Methods: Outpatient children (7–11 years) and adolescents (12–17 years) who met DSM-IV-TR criteria for MDD and had screening and baseline Children's Depression Rating Scale–Revised (CDRS-R) total scores >40 were randomly assigned to 8-week treatment with placebo, desvenlafaxine (25, 35, or 50 mg/d based on baseline weight), or fluoxetine (20 mg/d). The primary efficacy endpoint was change from baseline in CDRS-R total score at week 8, analyzed using a mixed-effects model for repeated measures. Secondary efficacy endpoints included week 8 Clinical Global Impressions–Severity, Clinical Global Impressions–Improvement (CGI-I), and response (CGI-I ≤ 2). Safety assessments included adverse events, physical and vital sign measurements, laboratory evaluations, electrocardiogram, and the Columbia-Suicide Severity Rating Scale. Results: The safety population included 339 patients (children, n = 130; adolescents, n = 209). The primary endpoint, change from baseline in CDRS-R total score at week 8, did not statistically separate from placebo, for either desvenlafaxine (adjusted mean [standard error] change, −22.6 [1.17]) or fluoxetine (−24.8 [1.17]; placebo, −23.1 [1.18]). Week 8 CGI-I response rates were significantly greater for fluoxetine (78.2%; p = 0.017) than for placebo (62.6%); desvenlafaxine (68.7%) did not differ from placebo. Other secondary outcomes were consistent with those obtained with CDRS-R. Rates of treatment-emergent adverse events were comparable among treatment groups (desvenlafaxine, 60.0%; placebo, 70.5%; and fluoxetine, 64.3%). Conclusion: Desvenlafaxine did not demonstrate efficacy for treating MDD in children and adolescents in this trial. Because neither desvenlafaxine nor the reference medication, fluoxetine, demonstrated a
Fluorine magnetic resonance spectroscopy measurement of brain fluvoxamine and fluoxetine in pediatric patients treated for pervasive developmental disorders.

PubMed

Strauss, Wayne L; Unis, Alan S; Cowan, Charles; Dawson, Geraldine; Dager, Stephen R

2002-05-01

Pediatric populations, including those with autistic disorder or other pervasive developmental disorders, increasingly are being prescribed selective serotonin reuptake inhibitors (SSRIs). Little is known about the age-related brain pharmacokinetics of SSRIs; there is a lack of data regarding optimal dosing of medications for children. The authors used fluorine magnetic resonance spectroscopy ((19)F MRS) to evaluate age effects on whole-brain concentrations of fluvoxamine and fluoxetine in children taking SSRIs. Twenty-one pediatric subjects with diagnoses of autistic disorder or other pervasive developmental disorders, 6-15 years old and stabilized with a consistent dose of fluvoxamine or fluoxetine, were recruited for the study; 16 successfully completed the imaging protocol. Whole-brain drug levels in this group were compared to similarly acquired data from 28 adults. A significant relationship between dose and brain drug concentration was observed for both drugs across the age range studied. Brain fluvoxamine concentration in the children was lower, consistent with a lower dose/body mass drug prescription; when brain concentration was adjusted for dose/mass, age effects were no longer significant. Brain fluoxetine concentration was similar between age groups; no significant age effects on brain fluoxetine drug levels remained after adjustment for dose/mass. Observations of brain fluoxetine bioavailability and elimination half-life also were similar between age groups. These findings suggest that fluvoxamine or fluoxetine prescriptions adjusted for dose/mass are an acceptable treatment approach for medicating children with autistic disorder or other pervasive developmental disorders. It must be determined whether these findings can be generalized to other pediatric populations.
Estradiol or fluoxetine alters depressive behavior and tryptophan hydroxylase in rat raphe.

PubMed

Yang, Fu-Zhong; Wu, Yan; Zhang, Wei-Guo; Cai, Yi-Yun; Shi, Shen-Xun

2010-03-10

The effects of 17beta-estradiol and fluoxetine on behavior of ovariectomized rats subjected to the forced swimming test and the expression of tryptophan hydroxylase (TPH) in dorsal and median raphe were investigated, respectively through time sampling technique of behavior scoring and immunohistochemistry. Both estradiol and fluoxetine increased swimming and decreased immobility in the forced swimming test. The forced swimming stress decreased integrated optical density of TPH-positive regions in dorsal and median raphe. Both estradiol and fluoxetine administration prevented integrated optical density of TPH-positive regions from being decreased by forced swimming stress. These observations suggest that both estradiol and fluoxetine have protective bearing on ovariectomized rats enduring forced swimming stress.
Fluoxetine Increases the Expression of miR-572 and miR-663a in Human Neuroblastoma Cell Lines.

PubMed

Mundalil Vasu, Mahesh; Anitha, Ayyappan; Takahashi, Taro; Thanseem, Ismail; Iwata, Keiko; Asakawa, Tetsuya; Suzuki, Katsuaki

2016-01-01

Evidence suggests neuroprotective effects of fluoxetine, a selective serotonin reuptake inhibitor (SSRI), on the developed neurons in the adult brain. In contrast, the drug may be deleterious to immature or undifferentiated neural cells, although the mechanism is unclear. Recent investigations have suggested that microRNAs (miRNA) may be critical for effectiveness of psychotropic drugs including SSRI. We investigated whether fluoxetine could modulate expressions of neurologically relevant miRNAs in two neuroblastoma SK-N-SH and SH-SY5Y cell lines. Initial screening results revealed that three (miR-489, miR-572 and miR-663a) and four (miR-320a, miR-489, miR-572 and miR-663a) miRNAs were up-regulated in SK-N-SH cells and SH-SY5Y cells, respectively, after 24 hours treatment of fluoxetine (1-25 μM). Cell viability was reduced according to the dose of fluoxetine. The upregulation of miR-572 and miR-663a was consistent in both the SH-SY5Y and SK-N-SH cells, confirmed by a larger scale culture condition. Our data is the first in vitro evidence that fluoxetine could increase the expression of miRNAs in undifferentiated neural cells, and that putative target genes of those miRNAs have been shown to be involved in fundamental neurodevelopmental processes.
Involvement of PI3K/Akt/FoxO3a and PKA/CREB Signaling Pathways in the Protective Effect of Fluoxetine Against Corticosterone-Induced Cytotoxicity in PC12 Cells.

PubMed

Zeng, Bingqing; Li, Yiwen; Niu, Bo; Wang, Xinyi; Cheng, Yufang; Zhou, Zhongzhen; You, Tingting; Liu, Yonggang; Wang, Haitao; Xu, Jiangping

2016-08-01

The selective serotonin reuptake inhibitor fluoxetine is neuroprotective in several brain injury models. It is commonly used to treat major depressive disorder and related conditions, but its mechanism of action remains incompletely understood. Activation of the phosphatidylinositol-3-kinase/protein kinase B/forkhead box O3a (PI3K/Akt/FoxO3a) and protein kinase A/cAMP-response element binding protein (PKA/CREB) signaling pathways has been strongly implicated in the pathogenesis of depression and might be the downstream target of fluoxetine. Here, we used PC12 cells exposed to corticosterone (CORT) to study the neuroprotective effects of fluoxetine and the involvement of the PI3K/Akt/FoxO3a and PKA/CREB signaling pathways. Our results show that CORT reduced PC12 cells viability by 70 %, and that fluoxetine showed a concentration-dependent neuroprotective effect. Neuroprotective effects of fluoxetine were abolished by inhibition of PI3K, Akt, and PKA using LY294002, KRX-0401, and H89, respectively. Treatment of PC12 cells with fluoxetine resulted in increased phosphorylation of Akt, FoxO3a, and CREB. Fluoxetine also dose-dependently rescued the phosphorylation levels of Akt, FoxO3a, and CREB, following administration of CORT (from 99 to 110, 56 to 170, 80 to 170 %, respectively). In addition, inhibition of PKA and PI3K/Akt resulted in decreased levels of p-CREB, p-Akt, and p-FoxO3a in the presence of fluoxetine. Furthermore, fluoxetine reversed CORT-induced upregulation of p53-upregulated modulator of apoptosis (Puma) and Bcl-2-interacting mediator of cell death (Bim) via the PI3K/Akt/FoxO3a signaling pathway. H89 treatment reversed the effect of fluoxetine on the mRNA level of brain-derived neurotrophic factor, which was decreased in the presence of CORT. Our data indicate that fluoxetine elicited neuroprotection toward CORT-induced cell death that involves dual regulation from PI3K/Akt/FoxO3a and PKA/CREB pathways.
Dose-dependent fluoxetine effects on boldness in male Siamese fighting fish.

PubMed

Dzieweczynski, Teresa L; Campbell, Brennah A; Kane, Jessica L

2016-03-01

As the use of pharmaceuticals and personal care products (PPCPs) continues to rise, these compounds enter the environment in increasing frequency. One such PPCP, fluoxetine, has been found in detectable amounts in aquatic ecosystems worldwide, where it may interfere with the behavior of exposed organisms. Fluoxetine exposure has been found to influence boldness and exploration in a range of fish species; however, how it might alter behavior in multiple contexts or over time is rarely examined. To this end, the effects of fluoxetine on boldness over time were studied in male Siamese fighting fish. Three different groups of males (0, 0.5 and 5 µg l(-1) fluoxetine) were tested in multiple boldness assays (empty tank, novel environment and shoal) once a week for 3 weeks to collect baseline measures and then at three different time points post-exposure. The effects of these varying exposure amounts on behavior were then examined for overall response, consistency and across-context correlations. Unexposed males were bolder in all contexts, were more consistent within a context, and had stronger between-context correlations than exposed males. Fluoxetine had dose-dependent effects on behavior, as males that received the higher dose exhibited greater behavioral effects. This study stresses the potential fitness consequences of fluoxetine exposure and suggests that examining behavioral effects of PPCPs under different dosing regimens and in multiple contexts is important to gain an increased understanding of how exposure affects behavior. © 2016. Published by The Company of Biologists Ltd.
Fluoxetine treatment abolishes the in vitro respiratory response to acidosis in neonatal mice.

PubMed

Voituron, Nicolas; Shvarev, Yuri; Menuet, Clément; Bevengut, Michelle; Fasano, Caroline; Vigneault, Erika; El Mestikawy, Salah; Hilaire, Gérard

2010-10-26

To secure pH homeostasis, the central respiratory network must permanently adapt its rhythmic motor drive to environment and behaviour. In neonates, it is commonly admitted that the retrotrapezoid/parafacial respiratory group of neurons of the ventral medulla plays the primary role in the respiratory response to acidosis, although the serotonergic system may also contribute to this response. Using en bloc medullary preparations from neonatal mice, we have shown for the first time that the respiratory response to acidosis is abolished after pre-treatment with the serotonin-transporter blocker fluoxetine (25-50 µM, 20 min), a commonly used antidepressant. Using mRNA in situ hybridization and immunohistology, we have also shown the expression of the serotonin transporter mRNA and serotonin-containing neurons in the vicinity of the RTN/pFRG of neonatal mice. These results reveal that the serotonergic system plays a pivotal role in pH homeostasis. Although obtained in vitro in neonatal mice, they suggest that drugs targeting the serotonergic system should be used with caution in infants, pregnant women and breastfeeding mothers.
Stress-induced activation of the brainstem Bcl-xL gene expression in rats treated with fluoxetine: correlations with serotonin metabolism and depressive-like behavior.

PubMed

Shishkina, Galina T; Kalinina, Tatyana S; Berezova, Inna V; Dygalo, Nikolay N

2012-01-01

Mechanisms underlying stress-induced depression and antidepressant drug action were shown to involve alterations in serotonergic (5-HT) neurotransmission and expression of genes coding for proteins associated with neurotrophic signaling pathways and cell-survival in the hippocampus and cortex. Expression of these genes in the brainstem containing 5-HT neurons may also be related to vulnerability or resilience to stress-related psychopathology. Here we investigated 5-HT markers and expression of genes for Brain-Derived Neurotrophic Factor (BDNF) and apoptotic proteins in the brainstem in relation to swim stress-induced behavioral despair. We found that anti-apoptotic Bcl-xL gene is sensitive to stress during the course of fluoxetine administration. Responsiveness of this gene to stress appeared concomitantly with an antidepressant-like effect of fluoxetine in the forced swim test. Bcl-xL transcript levels showed negative correlations with duration of immobility in the test and 5-HT turnover in the brainstem. In contrast, BDNF and pro-apoptotic protein Bax mRNA levels were unchanged by either fluoxetine or stress, suggesting specificity of Bcl-xL gene responses to these treatments. We also found that the levels of mRNAs for tryptophan hydroxylase-2 (TPH2) and 5-HT transporter (5-HTT) were significantly down-regulated following prolonged treatment with fluoxetine, but were not affected by stress. Unlike TPH2 and 5-HTT, 5-HT1A receptor mRNA levels were not altered by fluoxetine but significantly increased in response to swim stress. These data show that long-term fluoxetine treatment leads to changes in 5-HT and Bcl-xL responses to stress associated with antidepressant-like effects of the drug. This article is part of a Special Issue entitled 'Anxiety and Depression'. Copyright © 2011 Elsevier Ltd. All rights reserved.
The Aqueous Crude Extracts of Montanoa frutescens and Montanoa grandiflora Reduce Immobility Faster Than Fluoxetine Through GABAA Receptors in Rats Forced to Swim.

PubMed

Rodríguez-Landa, Juan Francisco; Cueto-Escobedo, Jonathan; Flores-Aguilar, Luis Ángel; Rosas-Sánchez, Gilberto Uriel; Rovirosa-Hernández, María de Jesús; García-Orduña, Francisco; Carro-Juárez, Miguel

2018-01-01

Montanoa frutescens and Montanoa grandiflora have been indistinctly used for centuries in traditional Mexican medicine for reproductive impairments, anxiety, and mood disorders. Preclinical studies support their aphrodisiac and anxiolytic properties, but their effects on mood are still unexplored. The effects of 25 and 50 mg/kg of M frutescens and M grandiflora extracts were evaluated on days 1, 7, 14, 21, and 28 of treatment, and compared with fluoxetine (1 mg/kg) and Remotiv (7.14 mg/kg) in Wistar rats. The participation of GABA A receptor in the effects produced by the treatments was explored. Montanoa extracts reduced immobility since day 1 of treatment, while fluoxetine and Remotiv required 14 days. The GABA A antagonism blocked the effects of Montanoa extracts, but not of fluoxetine or Remotiv. Montanoa extracts prevented quickly the stress-induced behaviors in the swimming test through action at the GABA A receptor, exerting a protective effect different to the typical antidepressants drugs.
On the interaction between fluoxetine and lipid membranes: Effect of the lipid composition

NASA Astrophysics Data System (ADS)

Pham, Vy T.; Nguyen, Trinh Q.; Dao, Uyen P. N.; Nguyen, Trang T.

2018-02-01

Molecular interaction between the antidepressant fluoxetine and lipid bilayers was investigated in order to provide insights into the drug's incorporation to lipid membranes. In particular, the effects of lipid's unsaturation degree and cholesterol content on the partitioning of fluoxetine into large unilamellar vesicles (LUVs) comprised of unsaturated 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC) and saturated 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) were evaluated using second derivative spectrophotometry and Attenuated total reflection-Fourier transform infrared spectroscopy (ATR-FTIR). It was found that fluoxetine partitioned to a greater extent into the liquid-crystalline DOPC LUVs than into the solid-gel DPPC LUVs. The lipid physical state dependence of drug partitioning was verified by increasing the temperature in which the partition coefficient of fluoxetine significantly increased upon the change of the lipid phase from solid-gel to liquid-crystalline. The incorporation of 28 mol% cholesterol into the LUVs exerted a significant influence on the drug partitioning into both DOPC and DPPC LUVs. The ATR-FTIR study revealed that fluoxetine perturbed the conformation of DOPC more strongly than that of DPPC due to the cis-double bonds in the lipid acyl chains. Fluoxetine possibly bound to the carbonyl moiety of the lipids through the hydrogen bonding formation while displaced some water molecules surrounding the PO2- regions of the lipid head groups. Cholesterol, however, could lessen the interaction between fluoxetine and the carbonyl groups of both DOPC and DPPC LUVs. These findings provided a better understanding of the role of lipid structure and cholesterol on the interaction between fluoxetine and lipid membranes, shedding more light into the drug's therapeutic action.
Mice with ablated adult brain neurogenesis are not impaired in antidepressant response to chronic fluoxetine.

PubMed

Jedynak, Paulina; Kos, Tomasz; Sandi, Carmen; Kaczmarek, Leszek; Filipkowski, Robert K

2014-09-01

The neurogenesis hypothesis of major depression has two main facets. One states that the illness results from decreased neurogenesis while the other claims that the very functioning of antidepressants depends on increased neurogenesis. In order to verify the latter, we have used cyclin D2 knockout mice (cD2 KO mice), known to have virtually no adult brain neurogenesis, and we demonstrate that these mice successfully respond to chronic fluoxetine. After unpredictable chronic mild stress, mutant mice showed depression-like behavior in forced swim test, which was eliminated with chronic fluoxetine treatment, despite its lack of impact on adult hippocampal neurogenesis in cD2 KO mice. Our results suggest that new neurons are not indispensable for the action of antidepressants such as fluoxetine. Using forced swim test and tail suspension test, we also did not observe depression-like behavior in control cD2 KO mice, which argues against the link between decreased adult brain neurogenesis and major depression. Copyright © 2014 Elsevier Ltd. All rights reserved.
Fluoxetine and its active metabolite norfluoxetine disrupt estrogen synthesis in a co-culture model of the feto-placental unit.

PubMed

Hudon Thibeault, Andrée-Anne; Laurent, Laetitia; Vo Duy, Sung; Sauvé, Sébastien; Caron, Patrick; Guillemette, Chantal; Sanderson, J Thomas; Vaillancourt, Cathy

2017-02-15

The effects of fluoxetine, one of the most prescribed selective serotonin-reuptake inhibitors (SSRIs) during pregnancy, and its active metabolite norfluoxetine were studied on placental aromatase (CYP19) and feto-placental steroidogenesis. Fluoxetine did not alter estrogen secretion in co-culture of fetal-like adrenocortical (H295R) and trophoblast-like (BeWo) cells used as a model of the feto-placental unit, although it induced CYP19 activity, apparently mediated by the serotonin (5-HT) 2A receptor/PKC signaling pathway. Norfluoxetine decreased estrogen secretion in the feto-placental co-culture and competitively inhibited catalytic CYP19 activity in BeWo cells. Decreased serotonin transporter (SERT) activity in the co-culture was comparable to 17β-estradiol treatment of BeWo cells. This work shows that the complex interaction of fluoxetine and norfluoxetine with placental estrogen production, involves 5-HT-dependent and -independent mechanisms. Considering the crucial role of estrogens during pregnancy, our results raise concern about the impact of SSRI treatment on placental function and fetal health. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.
Effects of fluoxetine on the amygdala and the hippocampus after administration of a single prolonged stress to male Wistar rates: In vivo proton magnetic resonance spectroscopy findings.

PubMed

Han, Fang; Xiao, Bing; Wen, Lili; Shi, Yuxiu

2015-05-30

Posttraumatic stress disorder (PTSD) is an anxiety- and memory-based disorder. The hippocampus and amygdala are key areas in mood regulation. Fluoxetine was found to improve the anxiety-related symptoms of PTSD patients. However, little work has directly examined the effects of fluoxetine on the hippocampus and the amygdala. In the present study, male Wistar rats received fluoxetine or vehicle after exposure to a single prolonged stress (SPS), an animal model of PTSD. In vivo proton magnetic resonance spectroscopy ((1)H-MRS) was performed -1, 1, 4, 7 and 14 days after SPS to examine the effects of fluoxetine on neurometabolite changes in amygdala, hippocampus and thalamus. SPS increased the N-acetylaspartate (NAA)/creatine (Cr) and choline moieties (Cho)/Cr ratios in the bilateral amygdala on day 4, decreased the NAA/Cr ratio in the left hippocampus on day 1, and increased both ratios in the right hippocampus on day 14. But no significant change was found in the thalamus. Fluoxetine treatment corrected the SPS increases in the NAA/Cr and Cho/Cr levels in the amygdala on day 4 and in the hippocampus on day 14, but it failed to normalise SPS-associated decreases in NAA/Cr levels in the left hippocampus on day 1. These results suggested that metabolic abnormalities in the amygdala and the hippocampus were involved in SPS, and different effects of fluoxetine in correcting SPS-induced neurometabolite changes among the three areas. These findings have implications for fluoxetine treatment in PTSD. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.
The effect of selective 5-hydroxytryptamine uptake inhibitors on 5-methoxy-N,N-dimethyltryptamine-induced ejaculation in the rat.

PubMed Central

Rényi, L.

1986-01-01

The ejaculatory response and the 5-hydroxytryptamine (5-HT) behavioural syndrome induced by 5-methoxy-N,N-dimethyltryptamine (5-MeODMT) (3 mg kg-1 i.p.) were studied following acute and repeated treatment of rats with the selective uptake inhibitors of 5-HT, fluoxetine, zimeldine, alaproclate, and citalopram. The oral doses used were based on the respective ED50 values for uptake inhibition. Acute doses of fluoxetine and zimeldine significantly reduced the ejaculatory response when given 48 h before 5-MeODMT. This blockade was prevented by treatment of the rats with the postsynaptic 5-HT receptor antagonist methergoline. An acute dose of fluoxetine given 7 and 14 days before 5-MeODMT significantly enhanced the ejaculatory response. On day 24, the response returned to the control level. Repeated treatment every second day (5 times over 9 days and 10 times over 19 days) with fluoxetine caused a longer blockade of the ejaculatory response and the sensitization of the response came later than after an acute dose. Parallel with the ejaculatory response three other components of the 5-HT behavioural syndrome also decreased significantly. Acute doses of alaproclate and citalopram significantly blocked the ejaculatory response at 1 h, but they failed to affect the response at any other time point after either acute or repeated treatment. Neither did these drugs attentuate the 5-HT syndrome. It is concluded that acute and repeated treatment of rats with different selective 5-HT uptake inhibitors does not produce a common alteration in 5-HT2-receptor functions. PMID:2939912
Assay of fluoxetine hydrochloride by titrimetric and HPLC methods.

PubMed

Bueno, F; Bergold, A M; Fröehlich, P E

2000-01-01

Two alternative methods were proposed to assay Fluoxetine Hydrochloride: a titrimetric method and another by HPLC using as mobile phase water pH 3.5: acetonitrile (65:35). These methods were applied to the determination of Fluoxetine as such or in formulations (capsules). The titrimetric method is an alternative for pharmacies and small industries. Both methods showed accuracy and precision and are an alternative to the official methods.

The effects of citalopram and fluoxetine on sexual behavior in healthy men: evidence of delayed ejaculation and unaffected sexual desire. A randomized, placebo-controlled, double-blind, double-dummy, parallel group study.

PubMed

Madeo, Bruno; Bettica, Paolo; Milleri, Stefano; Balestrieri, Antonio; Granata, Antonio R M; Carani, Cesare; Rochira, Vincenzo

2008-10-01

Selective serotonin reuptake inhibitors (SSRIs) are known to induce delayed orgasm and delayed ejaculation, while their effect on other aspects of sexual function, such as sexual motivation, arousal, and erectile function are unclear. In order to evaluate the effect of chronic administration of two SSRIs, citalopram and fluoxetine, on normal sexual function, we studied the parameters of male sexual behavior, erectile function, and ejaculation on 48 healthy male volunteers, aged 29.5 +/- 4.9, in a randomized, placebo-controlled, double-blind, double-dummy study. Methods. The subjects were randomized to receive placebo (16 subjects), or fluoxetine (20 mg/day) (16 subjects) or citalopram (20 mg/day) for the first week, and 40 mg/day in the following 3 weeks (16 subjects). Sexual function was investigated at the screening and at the end of the study by means of test of penile erection (TPE) and masturbation ejaculation latency time (MELT) performed during visual erotic stimulation, and at each visit by self-filled questionnaires (International Index Erectile Function [IIEF-15] and Golombock Rust Inventory of Sexual Satisfaction [GRISS]). All the erectile parameters, evaluated by means of RigiScan Plus during TPE, were not significantly different when both fluoxetine and citalopram were compared with placebo. A delay in the ejaculation time was observed both during citalopram and during fluoxetine treatment when compared with placebo, reaching a statistical significance only with citalopram. During the treatment with citalopram and fluoxetine, the IIEF-15 score of all items decreased except for those items related to sexual desire; however, the scores were significantly lower only for the citalopram treatment. The treatment with citalopram or with fluoxetine was confirmed to delay ejaculation, but was significant only for citalopram. Citalopram and fluoxetine did not affect sexual desire. Citalopram and fluoxetine did not directly affect penile erection as objectively
Dichotic listening tests of functional brain asymmetry predict response to fluoxetine in depressed women and men.

PubMed

Bruder, Gerard E; Stewart, Jonathan W; McGrath, Patrick J; Deliyannides, Deborah; Quitkin, Frederic M

2004-09-01

Patients having a depressive disorder vary widely in their therapeutic responsiveness to a selective serotonin reuptake inhibitor (SSRI), but there are no clinical predictors of treatment outcome. Studies using dichotic listening, electrophysiologic and neuroimaging measures suggest that pretreatment differences among depressed patients in functional brain asymmetry are related to responsiveness to antidepressants. Two new studies replicate differences in dichotic listening asymmetry between fluoxetine responders and nonresponders, and demonstrate the importance of gender in this context. Right-handed outpatients who met DSM-IV criteria for major depression, dysthymia, or depression not otherwise specified were tested on dichotic fused-words and complex tones tests before completing 12 weeks of fluoxetine treatment. Perceptual asymmetry (PA) scores were compared for 75 patients (38 women) who responded to treatment and 39 patients (14 women) who were nonresponders. Normative data were also obtained for 101 healthy adults (61 women). Patients who responded to fluoxetine differed from nonresponders and healthy adults in favoring left- over right-hemisphere processing of dichotic stimuli, and this difference was dependent on gender and test. Heightened left-hemisphere advantage for dichotic words in responders was present among women but not men, whereas reduced right-hemisphere advantage for dichotic tones in responders was present among men but not women. Pretreatment PA was also predictive of change in depression severity following treatment. Responder vs nonresponder differences for verbal dichotic listening in women and nonverbal dichotic listening in men are discussed in terms of differences in cognitive function, hemispheric organization, and neurotransmitter function.
Antidepressant effects of Kai-Xin-San in fluoxetine-resistant depression rats.

PubMed

Dong, X Z; Wang, D X; Lu, Y P; Yuan, S; Liu, P; Hu, Y

2017-08-17

This study aimed to investigate the antidepressant effect and the mechanism of action of Kai-Xin-San (KXS) in fluoxetine-resistant depressive (FRD) rats. Two hundred male Wistar rats weighing 200±10 g were exposed to chronic and unpredictable mild stresses (CUMS) for 4 weeks and given fluoxetine treatment simultaneously. The rats that did not show significant improvement in behavioral indexes were chosen as the FRD model rats. These rats were randomly divided into four groups: FRD model control; oral fluoxetine and aspirin; oral KXS at a dose of 338 mg·kg-1·day-1; and oral KXS at a dose of 676 mg·kg-1·day-1. Rats continued to be exposed to CUMS and underwent treatment once a day for 3 weeks, then cytokine (COX-2, IFN-γ, IL-1β, IL-2, IL-4, IL-6, IL-10, TGF-β, and TNF-α) levels in the hippocampus and serum, and organ coefficients were measured. Both doses of KXS improved the crossing and rearing frequencies, sucrose-preference index, and body weight in FRD rats. KXS at a dose of 338 mg·kg-1·day-1reduced COX-2, IL-2, IL-6, TNF-α levels, increased IL-10 level in the hippocampus, and reduced IL-2 and TNF-α levels in serum. KXS at a dose of 676 mg·kg-1·day-1reduced TNF-α level in the hippocampus, reduced IL-2 and TNF-α levels in serum, and increased IFN-γ and IL-10 levels in the hippocampus and serum. There were no significant differences in organ-coefficients of the spleen among and between groups. The results suggested that oral administration of KXS in FRD rats was effective in improving behavior disorders by influencing various inflammatory pathways.
Alterations on the morphology, nitric oxide synthesis and activity of platelets reproduced in rats as possible biomarkers for depression are reversed by fluoxetine.

PubMed

González-Trujano, María Eva; Alvarado-Vásquez, Noé; Mendoza-Sotelo, José; López, Guadalupe; Estrada-Camarena, Erika; Martínez-Mota, Lucia; Moreno, Julia

2012-08-01

Biochemical markers associated with the prognosis of depression in humans are being described in the literature, whereas experimental studies in animal models in search for antidepressant strategies are lacking. The aim of this study was to evaluate platelet morphology, platelet activity and nitric oxide (NO) synthesis as possible biomarkers of depressive-like behavior by using FST alone and in the presence of fluoxetine. Naïve rats were compared to those receiving vehicle or fluoxetine at 10mg/kg i.p. in acute, subchronic and chronic administration in the FST. After behavioral assessment, platelets were isolated from blood samples and analyzed by flow cytometry to determine the platelet mitochondrial membrane potential and NO synthesis. In addition, HPLC and electron microscopy were used to examine 5-HT and tryptophan levels and morphology of platelets, respectively. Rats receiving vehicle and exposed to FST showed depressive-like behavior at all the times tested; after chronic FST rats showed a similar pattern of alteration in platelet morphology and in the studied as possible biochemical markers as those previously recognized in depressive humans. Depressive-like behavior in rats exposed to FST was prevented in the presence of fluoxetine administration at all the times tested and associated with the prevention of alterations in platelet morphology, platelet activity and NO synthesis, and/or in 5-HT concentrations. The results of the present study suggest that platelet function and morphology might be relevant markers for the prognosis of depression and the search for functional treatments. Besides, the relevance of FST as model to study this psychiatric illness is reinforced. Copyright © 2012 Elsevier Inc. All rights reserved.
Fluoxetine Hydrochloride Enhances In Vitro Susceptibility to Chloroquine in Resistant Plasmodium falciparum

DTIC Science & Technology

1992-12-01

34AD"A 59 579 N.PAGE 10M07.""l kflll/IllI/ 1. AGENCY USE ONLv - 1 1 j 1 TT•PE DATES COVERD 4. TnE AN0 SUBTITI S. FUNDING NUMBERS Fluoxetine ...of currently available antimalarial drugs, such as chloroquine. We identified fluoxetine hydro- chloride (Prozac), a commonly prescribed antidepressant...locations confirmed our initial observations with a chloroquine-resistant P. falciparum clone, W2. Fluoxetine con- centrations of 500 nM were found to
Fluoxetine Blocks Nav1.5 Channels via a Mechanism Similar to That of Class 1 Antiarrhythmics

PubMed Central

Poulin, Hugo; Bruhova, Iva; Timour, Quadiri; Theriault, Olivier; Beaulieu, Jean-Martin; Frassati, Dominique

2014-01-01

The voltage-gated Nav1.5 channel is essential for the propagation of action potentials in the heart. Malfunctions of this channel are known to cause hereditary diseases. It is a prime target for class 1 antiarrhythmic drugs and a number of antidepressants. Our study investigated the Nav1.5 blocking properties of fluoxetine, a selective serotonin reuptake inhibitor. Nav1.5 channels were expressed in HEK-293 cells, and Na+ currents were recorded using the patch-clamp technique. Dose-response curves of racemic fluoxetine (IC50 = 39 μM) and its optical isomers had a similar IC50 [40 and 47 μM for the (+) and (−) isomers, respectively]. Norfluoxetine, a fluoxetine metabolite, had a higher affinity than fluoxetine, with an IC50 of 29 μM. Fluoxetine inhibited currents in a frequency-dependent manner, shifted steady-state inactivation to more hyperpolarized potentials, and slowed the recovery of Nav1.5 from inactivation. Mutating a phenylalanine (F1760) and a tyrosine (Y1767) in the S6 segment of domain (D) IV (DIVS6) significantly reduced the affinity of fluoxetine and its frequency-dependent inhibition. We used a noninactivating Nav1.5 mutant to show that fluoxetine displays open-channel block behavior. The molecular model of fluoxetine in Nav1.5 was in agreement with mutational experiments in which F1760 and Y1767 were found to be the key residues in binding fluoxetine. We concluded that fluoxetine blocks Nav1.5 by binding to the class 1 antiarrhythmic site. The blocking of cardiac Na+ channels should be taken into consideration when prescribing fluoxetine alone or in association with other drugs that may be cardiotoxic or for patients with conduction disorders. PMID:25028482
The effects of fluoxetine on the subjective and physiological effects of 3,4-methylenedioxymethamphetamine (MDMA) in humans.

PubMed

Tancer, Manuel; Johanson, Chris-Ellyn

2007-01-01

The purpose of this study was to investigate the role of serotonin (5-HT) in the effects of oral 3,4-methylenedioxymethamphetamine (MDMA) in humans. The subjective and physiological effects of 1.5 mg/kg MDMA were evaluated after 20 mg fluoxetine in eight recreational MDMA users in a double-blind, placebo-controlled study. During phase 1, participants were maintained on placebo for at least 5 days and tested with MDMA and placebo on separate sessions. In phase 2, the procedure was the same except fluoxetine was administered daily for at least 5 days. During sessions, placebo or fluoxetine was given 1 h before the session drug and effects were measured over the next 7 h. MDMA increased positive-like subjective effects on all the Addiction Research Center Inventory scales; Arousal, Elation, Positive Mood, and Vigor on the Profile of Mood States; Drug Liking, Friendly, Good Drug Effect, High, Stimulated, and Talkative on the Visual Analog Scale; and End-of-Session Liking and Crossover Point on the Multiple Choice Procedure. MDMA also increased measures of anxiety. On the Hallucinogenic Rating Scale, all scales except Volition were increased. MDMA also increased blood pressure and heart rate. Fluoxetine treatment attenuated most of the positive-like subjective effects including the Affect and Soma scales of the Hallucinogen Rating Scale. In addition, heart rate but not blood pressure increases were reduced. These results suggest that blockade of 5-HT reuptake by fluoxetine can dampen the effects of MDMA and further supports the role of 5-HT in its behavioral effects in humans.
Behavioral effects of chronic fluoxetine in BALB/cJ mice do not require adult hippocampal neurogenesis or the serotonin 1A receptor.

PubMed

Holick, Kerri A; Lee, Daniel C; Hen, René; Dulawa, Stephanie C

2008-01-01

We previously reported that chronic, but not subchronic, treatment with the selective serotonin reuptake inhibitor (SSRI) fluoxetine altered behavior in the forced swimming test (FST) in BALB/cJ mice. We now use this model to investigate mechanisms underlying the delayed onset of the behavioral response to antidepressants, specifically (1) adult hippocampal neurogenesis and (2) expression of the 5-HT1A receptor. Here, we show data validating this model of chronic antidepressant action. We found the FST to be selectively responsive to chronic administration of the SSRI fluoxetine (18 mg/kg/day) and the tricyclic antidepressant desipramine (20 mg/kg/day), but not to the antipsychotic haloperidol (1 mg/kg/day) in BALB/cJ mice. The behavioral effects of fluoxetine emerged by 12 days of treatment, and were affected neither by ablation of progenitor cells of the hippocampus nor by genetic deletion of the 5-HT1A receptor. The effect of fluoxetine in the BALB/cJ mice was also neurogenesis-independent in the novelty-induced hypophagia test. We also found that chronic fluoxetine does not induce an increase in cell proliferation or the number of young neurons as measured by BrdU and doublecortin immunolabeling, respectively, in BALB/cJ mice. These data are in contrast to our previous report using a different strain of mice (129SvEvTac). In conclusion, we find that BALB/cJ mice show a robust response to chronic SSRI treatment in the FST, which is not mediated by an increase in new neurons in the hippocampus, and does not require the 5-HT1A receptor. These findings suggest that SSRIs can produce antidepressant-like effects via distinct mechanisms in different mouse strains.
Fluoxetine augments ventilatory CO2 sensitivity in Brown Norway but not Sprague Dawley rats.

PubMed

Hodges, Matthew R; Echert, Ashley E; Puissant, Madeleine M; Mouradian, Gary C

2013-04-01

The Brown Norway (BN; BN/NHsdMcwi) rat exhibits a deficit in ventilatory CO2 sensitivity and a modest serotonin (5-HT) deficiency. Here, we tested the hypothesis that the selective serotonin reuptake inhibitor fluoxetine would augment CO2 sensitivity in BN but not Sprague Dawley (SD) rats. Ventilation during room air or 7% CO2 exposure was measured before, during and after 3 weeks of daily injections of saline or fluoxetine (10mg/(kgday)) in adult male BN and SD rats. Fluoxetine had minimal effects on room air breathing in BN and SD rats (p>0.05), although tidal volume (VT) was reduced in BN rats (p<0.05). There were also minimal effects of fluoxetine on CO2 sensitivity in SD rats, but fluoxetine increased minute ventilation, breathing frequency and VT during hypercapnia in BN rats (p<0.05). The augmented CO2 response was reversible upon withdrawal of fluoxetine. Brain levels of biogenic amines were largely unaffected, but 5-HIAA and the ratio of 5-HIAA/5-HT were reduced (p<0.05) consistent with selective and effective 5-HT reuptake inhibition. Thus, fluoxetine increases ventilatory CO2 sensitivity in BN but not SD rats, further suggesting altered 5-HT system function may contribute to the inherently low CO2 sensitivity in the BN rat. Copyright © 2013 Elsevier B.V. All rights reserved.
Fluoxetine induces vasodilatation of cerebral arterioles by co-modulating NO/muscarinic signalling

PubMed Central

Ofek, Keren; Schoknecht, Karl; Melamed-Book, Naomi; Heinemann, Uwe; Friedman, Alon; Soreq, Hermona

2012-01-01

Ischaemic stroke patients treated with Selective Serotonin Reuptake Inhibitors (SSRI) show improved motor, cognitive and executive functions, but the underlying mechanism(s) are incompletely understood. Here, we report that cerebral arterioles in the rat brain superfused with therapeutically effective doses of the SSRI fluoxetine showed consistent, dose-dependent vasodilatation (by 1.2 to 1.6-fold), suppressible by muscarinic and nitric oxide synthase (NOS) antagonists [atropine, NG-nitro-l-arginine methyl ester (l-NAME)] but resistant to nicotinic and serotoninergic antagonists (mecamylamine, methylsergide). Fluoxetine administered 10–30 min. following experimental vascular photo-thrombosis increased arterial diameter (1.3–1.6), inducing partial, but lasting reperfusion of the ischaemic brain. In brain endothelial b.End.3 cells, fluoxetine induced rapid muscarinic receptor-dependent increases in intracellular [Ca2+] and promoted albumin- and eNOS-dependent nitric oxide (NO) production and HSP90 interaction. In vitro, fluoxetine suppressed recombinant human acetylcholinesterase (rhAChE) activity only in the presence of albumin. That fluoxetine induces vasodilatation of cerebral arterioles suggests co-promotion of endothelial muscarinic and nitric oxide signalling, facilitated by albumin-dependent inhibition of serum AChE. PMID:22697296
Fluoxetine ameliorates cognitive impairments induced by chronic cerebral hypoperfusion via down-regulation of HCN2 surface expression in the hippocampal CA1 area in rats.

PubMed

Luo, Pan; Zhang, Xiaoxue; Lu, Yun; Chen, Cheng; Li, Changjun; Zhou, Mei; Lu, Qing; Xu, Xulin; Shen, Guanxin; Guo, Lianjun

2016-01-01

Chronic cerebral hypoperfusion (CCH) causes cognitive impairments and increases the risk of Alzheimer's disease (AD) and vascular dementia (VD) through several biologically plausible pathways, yet the underlying neurobiological mechanisms are still poorly understood. In this study, we investigated whether fluoxetine, a selective serotonin reuptake inhibitor (SSRI), could play a neuroprotective role against chronic cerebral hypoperfusion injury and to clarify underlying mechanisms of its efficacy. Rats were subjected to permanent bilateral occlusion of the common carotid arteries (two-vessel occlusion, 2VO). Two weeks later, rats were treated with 30 mg/kg fluoxetine (intragastric injection, i.g.) for 6 weeks. Cognitive function was evaluated by Morris water maze (MWM) and novel objects recognition (NOR) test. Long-term potentiation (LTP) was used to address the underlying synaptic mechanisms. Western blotting was used to quantify the protein levels. Our results showed that fluoxetine treatment significantly improved the cognitive impairments caused by 2VO, accompanied with a reversion of 2VO-induced inhibitory of LTP. Furthermore, 2VO caused an up-regulation of hyperpolarization-activated cyclic nucleotide-gated channel 2 (HCN2) surface expressions in the hippocampal CA1 area and fluoxetine also effectively recovered the disorder of HCN2 surface expressions, which may be a possible mechanism that fluoxetine treatment ameliorates cognitive impairments in rats with CCH. Copyright © 2015 Elsevier Inc. All rights reserved.
Serotonin transporter gene (SLC6A4) polymorphisms are associated with response to fluoxetine in south Indian major depressive disorder patients.

PubMed

Manoharan, Aarthi; Shewade, Deepak Gopal; Rajkumar, Ravi Philip; Adithan, Surendiran

2016-10-01

Up to 30-40 % of the major depressive disorder patients do not respond sufficiently to antidepressant treatment. Genetic variations in the serotonin transporter gene have been implicated in modulating treatment response to selective serotonin reuptake inhibitors, and this association is influenced by ethnicity. We investigated the influence of serotonin transporter gene variants 5-HTTLPR and rs25531 in Indian population on fluoxetine response. One hundred and two major depressive disorder patients were started on fluoxetine treatment and after 6 weeks, classified as responders (n = 56) and non-responders (n = 46) using Hamilton depression rating scale and genotyped. Fisher's exact test was used to compare genotype frequencies between responders and non-responders. One-way analysis of variance and student t test were used to compare the percentage reduction (week 0-6) in Hamilton depression rating scores between genotype and haplotype groups. We observed a significant association between LL genotype of 5-HTTLPR and fluoxetine treatment response (p = 0.0066, OR (95 %) = 4.0 (1.45-11.03)) but not with the functional groups of 5-HTTLPR -rs25531. However, there was a significant difference in percentage reduction in HAM-D scores (week 0-6) between 5-HTTLPR genotypes (LL vs. LS + SS, p = 0.0036; LL vs. LS, p = 0.0109) as well as the functionally grouped haplotypes of 5-HTTLPR -rs25531 (LALA carriers vs. non-carriers of LALA, p = 0.0118; LALA vs. LAS+ LALG, p = 0.0419). The LL genotype and LALA haplotype of SLC6A4 are associated with favorable treatment response to fluoxetine in south Indian major depression patients.
21 CFR 520.980 - Fluoxetine.

Code of Federal Regulations, 2010 CFR

2010-04-01

... FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) ANIMAL DRUGS, FEEDS, AND RELATED PRODUCTS ORAL DOSAGE FORM NEW ANIMAL DRUGS § 520.980 Fluoxetine. (a) Specifications. Each... conjunction with a behavior modification plan. (3) Limitations. Federal law restricts this drug to use by or...
21 CFR 520.980 - Fluoxetine.

Code of Federal Regulations, 2011 CFR

2011-04-01

... FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) ANIMAL DRUGS, FEEDS, AND RELATED PRODUCTS ORAL DOSAGE FORM NEW ANIMAL DRUGS § 520.980 Fluoxetine. (a) Specifications. Each... conjunction with a behavior modification plan. (3) Limitations. Federal law restricts this drug to use by or...
21 CFR 520.980 - Fluoxetine.

Code of Federal Regulations, 2014 CFR

2014-04-01

... FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) ANIMAL DRUGS, FEEDS, AND RELATED PRODUCTS ORAL DOSAGE FORM NEW ANIMAL DRUGS § 520.980 Fluoxetine. (a) Specifications. Each... conjunction with a behavior modification plan. (3) Limitations. Federal law restricts this drug to use by or...
21 CFR 520.980 - Fluoxetine.

Code of Federal Regulations, 2013 CFR

2013-04-01

... FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) ANIMAL DRUGS, FEEDS, AND RELATED PRODUCTS ORAL DOSAGE FORM NEW ANIMAL DRUGS § 520.980 Fluoxetine. (a) Specifications. Each... conjunction with a behavior modification plan. (3) Limitations. Federal law restricts this drug to use by or...
Fluoxetine normalizes disrupted light-induced entrainment, fragmented ultradian rhythms and altered hippocampal clock gene expression in an animal model of high trait anxiety- and depression-related behavior.

PubMed

Schaufler, Jörg; Ronovsky, Marianne; Savalli, Giorgia; Cabatic, Maureen; Sartori, Simone B; Singewald, Nicolas; Pollak, Daniela D

2016-01-01

Disturbances of circadian rhythms are a key symptom of mood and anxiety disorders. Selective serotonin reuptake inhibitors (SSRIs) - commonly used antidepressant drugs - also modulate aspects of circadian rhythmicity. However, their potential to restore circadian disturbances in depression remains to be investigated. The effects of the SSRI fluoxetine on genetically based, depression-related circadian disruptions at the behavioral and molecular level were examined using mice selectively bred for high anxiety-related and co-segregating depression-like behavior (HAB) and normal anxiety/depression behavior mice (NAB). The length of the circadian period was increased in fluoxetine-treated HAB as compared to NAB mice while the number of activity bouts and light-induced entrainment were comparable. No difference in hippocampal Cry2 expression, previously reported to be dysbalanced in untreated HAB mice, was observed, while Per2 and Per3 mRNA levels were higher in HAB mice under fluoxetine treatment. The present findings provide evidence that fluoxetine treatment normalizes disrupted circadian locomotor activity and clock gene expression in a genetic mouse model of high trait anxiety and depression. An interaction between the molecular mechanisms mediating the antidepressant response to fluoxetine and the endogenous regulation of circadian rhythms in genetically based mood and anxiety disorders is proposed.
Fluoxetine suppresses calcium signaling in human T lymphocytes through depletion of intracellular calcium stores.

PubMed

Gobin, V; De Bock, M; Broeckx, B J G; Kiselinova, M; De Spiegelaere, W; Vandekerckhove, L; Van Steendam, K; Leybaert, L; Deforce, D

2015-09-01

Selective serotonin reuptake inhibitors, such as fluoxetine, have recently been shown to exert anti-inflammatory and immunosuppressive effects. Although the effects on cytokine secretion, proliferation and viability of T lymphocytes have been extensively characterized, little is known about the mechanism behind these effects. It is well known that Ca(2+) signaling is an important step in the signaling transduction pathway following T cell receptor activation. Therefore, we investigated if fluoxetine interferes with Ca(2+) signaling in Jurkat T lymphocytes. Fluoxetine was found to suppress Ca(2+) signaling in response to T cell receptor activation. Moreover, fluoxetine was found to deplete intracellular Ca(2+) stores, thereby leaving less Ca(2+) available for release upon IP3- and ryanodine-receptor activation. The Ca(2+)-modifying effects of fluoxetine are not related to its capability to block the serotonin transporter, as even a large excess of 5HT did not abolish the effects. In conclusion, these data show that fluoxetine decreases IP3- and ryanodine-receptor mediated Ca(2+) release in Jurkat T lymphocytes, an effect likely to be at the basis of the observed immunosuppression. Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.
Serotonergic mediation of the effects of fluoxetine, but not desipramine, in the rat forced swimming test.

PubMed

Page, M E; Detke, M J; Dalvi, A; Kirby, L G; Lucki, I

1999-11-01

The forced swimming test (FST) is a behavioral test in rodents that predicts the clinical efficacy of many types of antidepressant treatments. Recently, a behavior sampling technique was developed that scores individual response categories, including swimming, climbing and immobility. Although all antidepressant drugs reduce immobility in the FST, at least two distinct active behavioral patterns are produced by pharmacologically selective antidepressant drugs. Serotonin-selective reuptake inhibitors increase swimming behavior, while drugs acting primarily to increase extracellular levels of norepinephrine or dopamine increase climbing behavior. Distinct patterns of active behaviors in the FST may be mediated by distinct neurotransmitters, but this has not been shown directly. The present study examined the role of serotonin in mediating active behaviors in the forced swimming test after treatment with two antidepressant drugs, the selective serotonin reuptake inhibitor, fluoxetine and the selective norepinephrine reuptake inhibitor, desipramine. Endogenous serotonin was depleted by administering para-cholorophenylalanine (PCPA, 150 mg/kg, IP.) to rats 72 h and 48 h prior to the swim test. Fluoxetine (10 mg/kg, SC) or desipramine (10 mg/kg, SC) was given three times over a 24-h period prior to the FST. Behavioral responses, including immobility, swimming and climbing, were counted during the 5-min test. Pretreatment with PCPA blocked fluoxetine-induced reduction in immobility and increase in swimming behavior during the FST. In contrast, PCPA pretreatment did not interfere with the ability of desipramine to reduce immobility and increase climbing behavior. Depletion of serotonin prevented the behavioral effects of the selective serotonin reuptake inhibitor fluoxetine in the rat FST. Furthermore, depletion of serotonin had no impact on the behavioral effects induced by the selective norepinephrine reuptake inhibitor, desipramine. The effects of antidepressant drugs
Fluoxetine Treatment Abolishes the In Vitro Respiratory Response to Acidosis in Neonatal Mice

PubMed Central

Voituron, Nicolas; Shvarev, Yuri; Menuet, Clément; Bevengut, Michelle; Fasano, Caroline; Vigneault, Erika; Mestikawy, Salah El; Hilaire, Gérard

2010-01-01

Background To secure pH homeostasis, the central respiratory network must permanently adapt its rhythmic motor drive to environment and behaviour. In neonates, it is commonly admitted that the retrotrapezoid/parafacial respiratory group of neurons of the ventral medulla plays the primary role in the respiratory response to acidosis, although the serotonergic system may also contribute to this response. Methodology/Principal Findings Using en bloc medullary preparations from neonatal mice, we have shown for the first time that the respiratory response to acidosis is abolished after pre-treatment with the serotonin-transporter blocker fluoxetine (25–50 µM, 20 min), a commonly used antidepressant. Using mRNA in situ hybridization and immunohistology, we have also shown the expression of the serotonin transporter mRNA and serotonin-containing neurons in the vicinity of the RTN/pFRG of neonatal mice. Conclusions These results reveal that the serotonergic system plays a pivotal role in pH homeostasis. Although obtained in vitro in neonatal mice, they suggest that drugs targeting the serotonergic system should be used with caution in infants, pregnant women and breastfeeding mothers. PMID:21048979

Effect of using fluoxetine at different time windows on neurological functional prognosis after ischemic stroke.

PubMed

Guo, Yi; He, Yitao; Tang, Bingshan; Ma, Kefu; Cai, Zhili; Zeng, Siling; Zhang, Ying; Jiang, Xin

2016-01-01

To evaluate the effect of using fluoxetine at different time intervals after ischemic stroke on neurological functional prognosis in China. The patients enrolled were randomly allocated to three groups. Group A received fluoxetine 20 mg/day immediately; group B received fluoxetine 20 mg/day 7 days after enrollment; and group C did not receive fluoxetine. The therapeutic duration of fluoxetine was 90 days and the follow-up period was 180 days. The mean NIHSS score at day 90 was significantly lower in group A than group C (P = 0.005), while at day 180, the mean score in group A was significantly lower than groups B and C (P = 0.035, P = 0.000), respectively. The mean BI score at day 90 was significantly higher in group A than group C (P = 0.001), while at day 180, the mean score in group A was significantly higher than groups B and C (P = 0.036, P = 0.000), respectively. Regression analysis indicated that lower NIHSS score and higher BI score at day 180 were attributed to the early administration of fluoxetine. In patients with ischemic stroke, early administration of fluoxetine may improve the neurological functional prognosis.
The role of clinical variables, neuropsychological performance and SLC6A4 and COMT gene polymorphisms on the prediction of early response to fluoxetine in major depressive disorder.

PubMed

Gudayol-Ferré, Esteve; Herrera-Guzmán, Ixchel; Camarena, Beatriz; Cortés-Penagos, Carlos; Herrera-Abarca, Jorge E; Martínez-Medina, Patricia; Cruz, David; Hernández, Sandra; Genis, Alma; Carrillo-Guerrero, Mariana Y; Avilés Reyes, Rubén; Guàrdia-Olmos, Joan

2010-12-01

Major depressive disorder (MDD) is treated with antidepressants, but only between 50% and 70% of the patients respond to the initial treatment. Several authors suggested different factors that could predict antidepressant response, including clinical, psychophysiological, neuropsychological, neuroimaging, and genetic variables. However, these different predictors present poor prognostic sensitivity and specificity by themselves. The aim of our work is to study the possible role of clinical variables, neuropsychological performance, and the 5HTTLPR, rs25531, and val108/58Met COMT polymorphisms in the prediction of the response to fluoxetine after 4weeks of treatment in a sample of patient with MDD. 64 patients with MDD were genotyped according to the above-mentioned polymorphisms, and were clinically and neuropsychologically assessed before a 4-week fluoxetine treatment. Fluoxetine response was assessed by using the Hamilton Depression Rating Scale. We carried out a binary logistic regression model for the potential predictive variables. Out of the clinical variables studied, only the number of anxiety disorders comorbid with MDD have predicted a poor response to the treatment. A combination of a good performance in variables of attention and low performance in planning could predict a good response to fluoxetine in patients with MDD. None of the genetic variables studied had predictive value in our model. The possible placebo effect has not been controlled. Our study is focused on response prediction but not in remission prediction. Our work suggests that the combination of the number of comorbid anxiety disorders, an attentional variable, and two planning variables makes it possible to correctly classify 82% of the depressed patients who responded to the treatment with fluoxetine, and 74% of the patients who did not respond to that treatment. Copyright © 2010 Elsevier B.V. All rights reserved.
Placebo-Controlled Study of Pimozide Augmentation of Fluoxetine in Body Dysmorphic Disorder

PubMed Central

Phillips, Katharine A.

2006-01-01

Objective Although body dysmorphic disorder often responds to serotonin reuptake inhibitors (SRIs), most patients do not respond or respond only partially. However, placebo-controlled studies of augmentation of SRIs have not been done. Furthermore, although 40%–50% of patients are delusional, studies of antipsychotic medications have not been done. Method Twenty-eight patients with body dysmorphic disorder or its delusional variant participated in an 8-week, placebo-controlled, double-blind, parallel-group study of pimozide augmentation of fluoxetine. Results Pimozide was not more effective than placebo: two (18.2%) of 11 subjects responded to pimozide and three (17.6%) of 17 subjects responded to placebo. There was no significant effect of baseline delusionality on endpoint severity of body dysmorphic disorder. Delusionality did not decrease significantly more with pimozide than placebo. Conclusions Pimozide augmentation of fluoxetine treatment for body dysmorphic disorder was not more effective than placebo, even in more delusional patients. Further studies of augmentation for SRIs are needed. PMID:15677604
An HDAC-dependent epigenetic mechanism that enhances the efficacy of the antidepressant drug fluoxetine

PubMed Central

Schmauss, C.

2015-01-01

Depression is a prevalent and debilitating psychiatric illnesses. However, currently prescribed antidepressant drugs are only efficacious in a limited group of patients. Studies on Balb/c mice suggested that histone deacetylase (HDAC) inhibition may enhance the efficacy of the widely-prescribed antidepressant drug fluoxetine. This study shows that reducing HDAC activity in fluoxetine-treated Balb/c mice leads to robust antidepressant and anxiolytic effects. While reducing the activity of class I HDACs 1 and 3 led to antidepressant effects, additional class II HDAC inhibition was necessary to exert anxiolytic effects. In fluoxetine-treated mice, HDAC inhibitors increased enrichment of acetylated histone H4 protein and RNA polymerase II at promotor 3 of the brain-derived neurotrophic factor (Bdnf) gene and increased Bdnf transcription from this promotor. Reducing Bdnf-stimulated tropomyosin kinase B receptor activation in fluoxetine-treated mice with low HDAC activity abolished the behavioral effects of fluoxetine, suggesting that the HDAC-triggered epigenetic stimulation of Bdnf expression is critical for therapeutic efficacy. PMID:25639887
A Double-Blind Efficacy and Safety Study of Duloxetine Fixed Doses in Children and Adolescents with Major Depressive Disorder

PubMed Central

Emslie, Graham J.; Zhang, Qi; Pangallo, Beth A.; Bangs, Mark E.; March, John S.

2014-01-01

Abstract Objective: The purpose of this study was to evaluate the efficacy and safety of duloxetine fixed dose in the treatment of children (7–11 years) and adolescents (12–17 years) with major depressive disorder (MDD). Methods: Patients (n=463) in this 36 week study (10 week acute and 26 week extension treatment) received duloxetine 60 mg QD (n=108), duloxetine 30 mg QD (n=116), fluoxetine 20 mg QD (n=117, active control), or placebo (n=122). Measures included: Children's Depression Rating Scale-Revised (CDRS-R), treatment-emergent adverse events (TEAEs), and Columbia-Suicide Severity Rating Scale (C-SSRS). Results: Neither active drug (duloxetine or fluoxetine) separated significantly (p<0.05) from placebo on mean change from baseline to end-point (10 weeks) on the CDRS-R total score. Total TEAEs and discontinuation for AEs were significantly (p<0.05) higher only for the duloxetine 60 mg group versus the placebo group during acute treatment. No clinically significant electrocardiogram (ECG) or laboratory abnormalities were observed, and no completed suicides or deaths occurred during the study. A total of 7 (6.7%) duloxetine 60 mg, 6 (5.2%) duloxetine 30 mg, 9 (8.0%) fluoxetine, and 11 (9.4%) placebo patients had worsening of suicidal ideation from baseline during acute treatment. Of the patients with suicidal ideation at baseline, 13/16 (81%) duloxetine 60 mg, 16/17 (94%) duloxetine 30 mg, 11/16 (69%) fluoxetine, and 13/15 (87%) placebo had improvement in suicidal ideation at end-point during acute treatment. One fluoxetine, one placebo, and six duloxetine patients had treatment-emergent suicidal behavior during the 36 week study. Conclusions: Trial results were inconclusive, as neither the investigational drug (duloxetine) nor the active control (fluoxetine) separated from placebo on the CDRS-R at 10 weeks. No new duloxetine safety signals were identified relative to those seen in adults. Clinical Trial Registry Number (www
A double-blind efficacy and safety study of duloxetine fixed doses in children and adolescents with major depressive disorder.

PubMed

Emslie, Graham J; Prakash, Apurva; Zhang, Qi; Pangallo, Beth A; Bangs, Mark E; March, John S

2014-05-01

The purpose of this study was to evaluate the efficacy and safety of duloxetine fixed dose in the treatment of children (7-11 years) and adolescents (12-17 years) with major depressive disorder (MDD). Patients (n=463) in this 36 week study (10 week acute and 26 week extension treatment) received duloxetine 60 mg QD (n=108), duloxetine 30 mg QD (n=116), fluoxetine 20 mg QD (n=117, active control), or placebo (n=122). Measures included: Children's Depression Rating Scale-Revised (CDRS-R), treatment-emergent adverse events (TEAEs), and Columbia-Suicide Severity Rating Scale (C-SSRS). Neither active drug (duloxetine or fluoxetine) separated significantly (p<0.05) from placebo on mean change from baseline to end-point (10 weeks) on the CDRS-R total score. Total TEAEs and discontinuation for AEs were significantly (p<0.05) higher only for the duloxetine 60 mg group versus the placebo group during acute treatment. No clinically significant electrocardiogram (ECG) or laboratory abnormalities were observed, and no completed suicides or deaths occurred during the study. A total of 7 (6.7%) duloxetine 60 mg, 6 (5.2%) duloxetine 30 mg, 9 (8.0%) fluoxetine, and 11 (9.4%) placebo patients had worsening of suicidal ideation from baseline during acute treatment. Of the patients with suicidal ideation at baseline, 13/16 (81%) duloxetine 60 mg, 16/17 (94%) duloxetine 30 mg, 11/16 (69%) fluoxetine, and 13/15 (87%) placebo had improvement in suicidal ideation at end-point during acute treatment. One fluoxetine, one placebo, and six duloxetine patients had treatment-emergent suicidal behavior during the 36 week study. Trial results were inconclusive, as neither the investigational drug (duloxetine) nor the active control (fluoxetine) separated from placebo on the CDRS-R at 10 weeks. No new duloxetine safety signals were identified relative to those seen in adults. Clinical Trial Registry Number ( www.ClinicalTrials.gov ): NCT00849693.
Biodegradability of fluoxetine, mefenamic acid, and metoprolol using different microbial consortiums.

PubMed

Velázquez, Yolanda Flores; Nacheva, Petia Mijaylova

2017-03-01

The biodegradation of fluoxetine, mefenamic acid, and metoprolol using ammonium-nitrite-oxidizing consortium, nitrite-oxidizing consortium, and heterotrophic biomass was evaluated in batch tests applying different retention times. The ammonium-nitrite-oxidizing consortium presented the highest biodegradation percentages for mefenamic acid and metoprolol, of 85 and 64% respectively. This consortium was also capable to biodegrade 79% of fluoxetine. The heterotrophic consortium showed the highest ability to biodegrade fluoxetine reaching 85%, and it also had a high potential for biodegrading mefenamic acid and metoprolol, of 66 and 58% respectively. The nitrite-oxidizing consortium presented the lowest biodegradation of the three pharmaceuticals, of less than 48%. The determination of the selected pharmaceuticals in the dissolved phase and in the biomass indicated that biodegradation was the major removal mechanism of the three compounds. Based on the obtained results, the biodegradation kinetics was adjusted to pseudo-first-order for the three pharmaceuticals. The values of k biol for fluoxetine, mefenamic acid, and metoprolol determined with the three consortiums indicated that ammonium-nitrite-oxidizing and heterotrophic biomass allow a partial biodegradation of the compounds, while no substantial biodegradation can be expected using nitrite-oxidizing consortium. Metoprolol was the less biodegradable compound. The sorption of fluoxetine and mefenamic acid onto biomass had a significant contribution for their removal (6-14%). The lowest sorption coefficients were obtained for metoprolol indicating that the sorption onto biomass is poor (3-4%), and the contribution of this process to the global removal can be neglected.
Fluoxetine and premature ejaculation: a double-blind, crossover, placebo-controlled study.

PubMed

Haensel, S M; Klem, T M; Hop, W C; Slob, A K

1998-02-01

The purpose of this study was to investigate the effect of fluoxetine on sexual function in men with premature ejaculation and/or erectile dysfunction and control subjects in a prospective, double-blind, placebo-controlled, crossover study. There were four groups: (1) premature ejaculation (PE, N = 9); (2) premature ejaculation and erectile dysfunction (PE/ED, N = 9); (3) erectile dysfunction (ED, N = 7); and (4) healthy, sexually functional control subjects (N = 15). The study consisted of three 4-week periods: fluoxetine, washout, and placebo (or vice versa). Fluoxetine began at 5 mg/day for 2 weeks, followed by 10 mg/day for 2 weeks. At weeks 0, 4, 8, and 12, subjects visited the laboratory for evaluation of sexual function and assessment of erectile response, ejaculation, and sexual arousal to visual erotic stimulation without and with concomitant vibrotactile stimulation to the penis. At home, daily logs for sexual activities and feelings of well-being were maintained, and nocturnal penile tumescence was measured. The latency to ejaculation increased significantly in the PE/ED group (p = 0.03) and in the PE and the PE/ED group taken together (p = 0.007) but not in the PE group alone. Fluoxetine stimulated objectively but not subjectively measured erectile response during laboratory assessment in all groups. No major side effects were reported. In conclusion, fluoxetine (5-10 mg/day) was effective in increasing latency to ejaculation in patients with PE (PE and PE/ED groups combined).
Fluoxetine Induces Proliferation and Inhibits Differentiation of Hypothalamic Neuroprogenitor Cells In Vitro

PubMed Central

Sousa-Ferreira, Lígia; Aveleira, Célia; Botelho, Mariana; Álvaro, Ana Rita; Pereira de Almeida, Luís; Cavadas, Cláudia

2014-01-01

A significant number of children undergo maternal exposure to antidepressants and they often present low birth weight. Therefore, it is important to understand how selective serotonin reuptake inhibitors (SSRIs) affect the development of the hypothalamus, the key center for metabolism regulation. In this study we investigated the proliferative actions of fluoxetine in fetal hypothalamic neuroprogenitor cells and demonstrate that fluoxetine induces the proliferation of these cells, as shown by increased neurospheres size and number of proliferative cells (Ki-67+ cells). Moreover, fluoxetine inhibits the differentiation of hypothalamic neuroprogenitor cells, as demonstrated by decreased number of mature neurons (Neu-N+ cells) and increased number of undifferentiated cells (SOX-2+ cells). Additionally, fluoxetine-induced proliferation and maintenance of hypothalamic neuroprogenitor cells leads to changes in the mRNA levels of appetite regulator neuropeptides, including Neuropeptide Y (NPY) and Cocaine-and-Amphetamine-Regulated-Transcript (CART). This study provides the first evidence that SSRIs affect the development of hypothalamic neuroprogenitor cells in vitro with consequent alterations on appetite neuropeptides. PMID:24598761
Fluoxetine Ameliorates Behavioral and Neuropathological Deficits in a Transgenic Model Mouse of α-synucleinopathy

PubMed Central

Ubhi, Kiren; Inglis, Chandra; Mante, Michael; Patrick, Christina; Adame, Anthony; Spencer, Brian; Rockenstein, Edward; May, Verena; Winkler, Juergen; Masliah, Eliezer

2013-01-01

The term α-synucleinopathies refers to a group of age-related neurological disorders including Parkinson’s disease (PD), Dementia with Lewy Bodies (DLB) and Multiple System Atrophy (MSA) that display an abnormal accumulation of alpha-synuclein (α-syn). In contrast to the neuronal α-syn accumulation observed in PD and DLB, MSA is characterized by a widespread oligodendrocytic α-syn accumulation. Transgenic mice expressing human α-syn under the oligodendrocyte-specific myelin basic protein promoter (MBP1-hαsyn tg mice) model many of the behavioral and neuropathological alterations observed in MSA. Fluoxetine, a selective serotonin reuptake inhibitor, has been shown to be protective in toxin-induced models of PD, however its effects in an in vivo transgenic model of α-synucleinopathy remain unclear. In this context, this study examined the effect of fluoxetine in the MBP1-hαsyn tg mice, a model of MSA. Fluoxetine adminstration ameliorated motor deficits in the MBP1-hαsyn tg mice, with a concomitant decrease in neurodegenerative pathology in the basal ganglia, neocortex and hippocampus. Fluoxetine adminstration also increased levels of the neurotrophic factors, GDNF (glial-derived neurotrophic factor) and BDNF (brain-derived neurotrophic factor) in the MBP1-hαsyn tg mice compared to vehicle-treated tg mice. This fluoxetine-induced increase in GDNF and BDNF protein levels was accompanied by activation of the ERK signaling pathway. The effects of fluoxetine adminstration on myelin and serotonin markers were also examined. Collectively these results indicate that fluoxetine may represent a novel therapeutic intervention for MSA and other neurodegenerative disorders. PMID:22281106
Fluoxetine coupled with zinc in a chronic mild stress model of depression: Providing a reservoir for optimum zinc signaling and neuronal remodeling.

PubMed

Omar, Nesreen Nabil; Tash, Reham Fathy

2017-09-01

Recently, depression has been envisioned as more than an alteration in neurotransmitters centered around receptor signaling pathways. Consequently, the precise mechanisms of selective serotonin reuptake inhibitor (SSRI) antidepressant drugs such as fluoxetine are being revisited. Zinc is a trace element that has been long implicated in the psychopathology and therapy of depression. Zinc has been found to be sequestered and dispensed during stress and inflammation through a family of proteins called metallothioneins (MTs). In addition, MTs are well known for their antioxidant and therefore cytoprotective action. Changes in MTs, their upstream regulators and downstream effectors in response to fluoxetine have not been yet studied. The aim of the present study is to examine whether depression-induced changes in protein levels and mRNA levels of nuclear factor-erythroid 2-related factor 2 (Nrf2), MTs, antioxidant defensive enzyme heme oxygenase (HO-1), zinc-specific receptor GPR39 and brain derived neurotrophic factor (BDNF) in the hippocampus can be reversed by fluoxetine treatment, zinc supplementation or a combination of the two. The present study investigated the effect of chronic (4weeks) combined treatment with zinc hydroaspartate (15mg/kg) and fluoxetine (10mg/kg) on a chronic mild stress model (CMS) in male Sprague-Dawley rats. Hippocampal mRNA and protein levels of Nrf2, HO-1, MTs, GPR39 (protein level only) and BDNF were significantly higher in response to a combined therapy of fluoxetine and zinc than to either monotherapy. Additionally, HO-1 and MTs gene expression was correlated with that of Nrf2 in the FLX-only group. Fluoxetine therapy activated the expression of MTs and HO-1 through an Nrf2-dependent pathway. When FLX was escorted by zinc, activated MTs had a positive impact on BDNF through the zinc signaling receptor GPR39, resulting in general improvement in neuronal plasticity as well as reduction of neuronal atrophy and neuronal cell loss. Copyright
Carbodithioic acid esters of fluoxetine, a novel class of dual-function spermicides.

PubMed

Kiran Kumar, S T V S; Kumar, Lalit; Sharma, Vishnu L; Jain, Ashish; Jain, Rajeev K; Maikhuri, Jagdamba P; Kumar, Manish; Shukla, Praveen K; Gupta, Gopal

2008-10-01

Carbodithioic acid esters of fluoxetine have been prepared by replacing the methylamino function in aminopropane chain with carbodithioic acid ester group and by adding various S-2-hydroxypropyl ester of dialkyl carbodithioic acid at 3-methylamino group. Some of these compounds showed spermicidal, antifungal and anti-Trichomonas activities. The study revealed that incorporation of carbodithioic acid residue directly into fluoxetine structure leads to compounds with better antifungal and anti-Trichomonas activities, and N-methyl-[3-phenyl-3-(4-trifluoromethyl-phenoxy)-propyl]carbodithioic acid S-(2-pyrrolidino-ethyl) ester (14) has shown better profile than both fluoxetine and nonoxynol-9. Further lead optimization may yield a potent dual-function spermicide.
Behavioral, endocrine, and neuronal alterations in zebrafish (Danio rerio) following sub-chronic coadministration of fluoxetine and ketamine.

PubMed

Pittman, Julian; Hylton, Andrew

2015-12-01

Most existing pharmacological treatments have focused on the "monoamine hypothesis" for targeted drug design for major depressive disorder (MDD). Many of these medications have a delayed onset-of-action and limited efficacy. Antidepressants with principal targets outside the monoamine system may offer the potential for more rapid activity with improved therapeutic benefit. Growing evidence suggests that the glutamatergic system is uniquely central to the neurobiology and treatment of MDD. Ketamine (Ketalar®) is a non-competitive glutamatergic antagonist classically used to induce sedation. However, preliminary clinical evidence has been promising with regard to its rapidly acting antidepressant profile. Zebrafish (Danio rerio) have emerged as a promising new animal model to screen the effects of numerous psychotropic compounds. This study aimed to determine if a sub-chronic low (sub-anesthetic) dose of ketamine could be used to augment the antidepressant effects of the widely used antidepressant fluoxetine (Prozac®) in adult zebrafish, employing an ethanol withdrawal model. Sub-chronic exposure to dosages of 100μg/L fluoxetine and 20mg/L of ketamine reduced anxiety/depression-like behaviors, leads to upregulation of serotonin synthesis and elevated whole-body cortisol levels. These results demonstrate the utility of zebrafish as a model for neuropharmacological research, and the possible efficacy of fluoxetine and ketamine coadministration. Copyright © 2015 Elsevier Inc. All rights reserved.
Effects of fluoxetine on CRF and CRF1 expression in rats exposed to the learned helplessness paradigm.

PubMed

Fernández Macedo, Georgina Valeria; Cladouchos, María Laura; Sifonios, Laura; Cassanelli, Pablo Martín; Wikinski, Silvia

2013-02-01

Stress is a common antecedent reported by people suffering major depression. In these patients, extrahypothalamic brain areas, like the hippocampus and basolateral amygdala (BLA), have been found to be affected. The BLA synthesizes CRF, a mediator of the stress response, and projects to hippocampus. The main hippocampal target for this peptide is the CRF subtype 1 receptor (CRF1). Evidence points to a relationship between dysregulation of CRF/CRF1 extrahypothalamic signaling and depression. Because selective serotonin reuptake inhibitors (SSRIs) are the first-line pharmacological treatment for depression, we investigated the effect of chronic treatment with the SSRI fluoxetine on long-term changes in CRF/CRF1 signaling in animals showing a depressive-like behavior. Male Wistar rats were exposed to the learned helplessness paradigm (LH). After evaluation of behavioral impairment, the animals were treated with fluoxetine (10 mg/kg i.p.) or saline for 21 days. We measured BLA CRF expression with RT-PCR and CRF1 expression in CA3 and the dentate gyrus of the hippocampus with in situ hybridization. We also studied the activation of one of CRF1's major intracellular signaling targets, the extracellular signal-related kinases 1 and 2 (ERK1/2) in CA3. In saline-treated LH animals, CRF expression in the BLA increased, while hippocampal CRF1 expression and ERK1/2 activation decreased. Treatment with fluoxetine reversed the changes in CRF and CRF1 expressions, but not in ERK1/2 activation. In animals exposed to the learned helplessness paradigm, there are long-term changes in CRF and CRF1 expression that are restored with a behaviorally effective antidepressant treatment.
Cost-effectiveness and cost-utility of cognitive therapy, rational emotive behavioral therapy, and fluoxetine (Prozac) in treating depression: a randomized clinical trial.

PubMed

Sava, Florin A; Yates, Brian T; Lupu, Viorel; Szentagotai, Aurora; David, Daniel

2009-01-01

Cost-effectiveness and cost-utility of cognitive therapy (CT), rational emotive behavioral therapy (REBT), and fluoxetine (Prozac) for major depressive disorder (MDD) were compared in a randomized clinical trial with a Romanian sample of 170 clients. Each intervention was offered for 14 weeks, plus three booster sessions. Beck Depression Inventory (BDI) scores were obtained prior to intervention, 7 and 14 weeks following the start of intervention, and 6 months following completion of intervention. CT, REBT, and fluoxetine did not differ significantly in changes in the BDI, depression-free days (DFDs), or Quality-Adjusted Life Years (QALYs). Average BDI scores decreased from 31.1 before treatment to 9.7 six months following completion of treatment. Due to lower costs, both psychotherapies were more cost-effective, and had better cost-utility, than pharmacotherapy: median $26.44/DFD gained/month for CT and $23.77/DFD gained/month for REBT versus $34.93/DFD gained/month for pharmacotherapy, median $/QALYs=$1,638, $1,734, and $2,287 for CT, REBT, and fluoxetine (Prozac), respectively. (c) 2008 Wiley Periodicals, Inc.
Sex-dependent effects of fluoxetine and triiodothyronine in the forced swim test in rats.

PubMed

Lifschytz, Tzuri; Shalom, Galit; Lerer, Bernard; Newman, Michael E

2006-02-01

The effects of triiodothyronine (T3) and fluoxetine, administered separately and combined, on behavior of male and female rats in the forced swim test, a procedure for screening antidepressant-like activity, were determined. There were no consistent effects of low doses of fluoxetine (5 mg/kg) or T3 (20 microg/kg), administered daily for 2 weeks. Fluoxetine administered daily at 10 mg/kg for 7 days reduced immobility and increased active behaviors in male rats, but had no effects in female rats. The effects of fluoxetine in male rats were not potentiated by T3. In female rats, T3 at 100 microg/kg given daily for 7 days decreased immobility and increased swimming when these were measured 72 h after the last injection, but not when measurements were performed at an earlier time point. These results provide some support from an animal model for the efficacy of T3 as antidepressant therapy in female patients, but do not provide support for the augmentation and acceleration effects seen clinically when T3 is used in conjunction with established antidepressants such as fluoxetine.
Differential Rearing Alters Forced Swim Test Behavior, Fluoxetine Efficacy, and Post-Test Weight Gain in Male Rats.

PubMed

Arndt, David L; Peterson, Christy J; Cain, Mary E

2015-01-01

Environmental factors play a key role in the etiology of depression. The rodent forced swim test (FST) is commonly used as a preclinical model of depression, with increases in escape-directed behavior reflecting antidepressant effects, and increases in immobility reflecting behavioral despair. Environmental enrichment leads to serotonergic alterations in rats, but it is unknown whether these alterations may influence the efficacy of common antidepressants. Male Sprague-Dawley rats were reared in enriched (EC), standard (SC), or isolated (IC) conditions. Following the rearing period, fluoxetine (10 or 20 mg/kg, i.p.) was administered 23.5 hrs, 5 hrs, and 1 hr before locomotor and FST measures. Following locomotor testing and FST exposure, rats were weighed to assess fluoxetine-, FST-, and environmental condition-induced moderations in weight gain. Results revealed an antidepressant effect of environmental enrichment and a depressant effect of isolation. Regardless of significant fluoxetine effects on locomotor activity, fluoxetine generally decreased swimming and increased immobility in all three environmental conditions, with IC-fluoxetine (10 mg/kg) rats and EC-fluoxetine (20 mg/kg) rats swimming less than vehicle counterparts. Subchronic 20 mg/kg fluoxetine also induced significant weight loss, and differential rearing appeared to moderate weight gain following FST stress. These results suggest that differential rearing has the ability to alter FST behaviors, fluoxetine efficacy, and post-stressor well-being. Moreover, 20 mg/kg fluoxetine, administered subchronically, may lead to atypical effects of those commonly observed in the FST, highlighting the importance and impact of both environmental condition and dosing regimen in common animal models of depression.
Differential Rearing Alters Forced Swim Test Behavior, Fluoxetine Efficacy, and Post-Test Weight Gain in Male Rats

PubMed Central

Arndt, David L.; Peterson, Christy J.; Cain, Mary E.

2015-01-01

Environmental factors play a key role in the etiology of depression. The rodent forced swim test (FST) is commonly used as a preclinical model of depression, with increases in escape-directed behavior reflecting antidepressant effects, and increases in immobility reflecting behavioral despair. Environmental enrichment leads to serotonergic alterations in rats, but it is unknown whether these alterations may influence the efficacy of common antidepressants. Male Sprague-Dawley rats were reared in enriched (EC), standard (SC), or isolated (IC) conditions. Following the rearing period, fluoxetine (10 or 20 mg/kg, i.p.) was administered 23.5 hrs, 5 hrs, and 1 hr before locomotor and FST measures. Following locomotor testing and FST exposure, rats were weighed to assess fluoxetine-, FST-, and environmental condition-induced moderations in weight gain. Results revealed an antidepressant effect of environmental enrichment and a depressant effect of isolation. Regardless of significant fluoxetine effects on locomotor activity, fluoxetine generally decreased swimming and increased immobility in all three environmental conditions, with IC-fluoxetine (10 mg/kg) rats and EC-fluoxetine (20 mg/kg) rats swimming less than vehicle counterparts. Subchronic 20 mg/kg fluoxetine also induced significant weight loss, and differential rearing appeared to moderate weight gain following FST stress. These results suggest that differential rearing has the ability to alter FST behaviors, fluoxetine efficacy, and post-stressor well-being. Moreover, 20 mg/kg fluoxetine, administered subchronically, may lead to atypical effects of those commonly observed in the FST, highlighting the importance and impact of both environmental condition and dosing regimen in common animal models of depression. PMID:26154768
A patient with coexisting narcolepsy and morbid jealousy showing favourable response to fluoxetine.

PubMed Central

Wing, Y. K.; Lee, S.; Chiu, H. F.; Ho, C. K.; Chen, C. N.

1994-01-01

A 37 year old Chinese man suffered from coexisting narcolepsy and morbid jealousy which were precipitated by head injury 5 years previously. Fluoxetine 20 mg/day reduced his narcoleptic symptoms and morbid jealousy but not his sleepiness. On defaulting treatment, the patient's symptoms and marital problem recurred. A common central serotonin disturbance might be involved in mediating the sleep disorder and associated psychopathology. PMID:8140016
Paracetamol potentiates the antidepressant-like and anticompulsive-like effects of fluoxetine.

PubMed

Manna, Shyamshree S S; Umathe, Sudhir N

2015-04-01

Recent studies suggest the possible involvement of serotonergic and endocannabinoid systems in analgesic, anxiolytic, and anticonvulsant-like actions of paracetamol. Considering the fact that these systems play intricate roles in affective disorders, we investigated the effects of paracetamol in depression-like and compulsion-like behavior. Swiss mice (20-22 g) were subjected to forced swim, tail suspension, or marble-burying tests after an injection of paracetamol either alone or in the presence of AM251 (a CB1 antagonist), fenclonine (pCPA: a 5-HT synthesis inhibitor), AM404 (anandamide uptake inhibitor) or fluoxetine. Paracetamol dose dependently (50-400 mg/kg) decreased depressive and compulsive behaviors. These effects were comparable to those of fluoxetine (5, 10, or 20 mg/kg) and AM404 (10 or 20 mg/kg). Interestingly, fenclonine pretreatment completely abolished the effects of a 50 mg/kg dose of paracetamol. However, similar effects were not observed in AM251-pretreated mice at the same dose. In contrast, AM251 completely antagonized the effects of the 400 mg/kg dose, which was otherwise partially blocked in fenclonine-treated mice. Similar sets of results were observed with fluoxetine and AM404. Thus, it appears that paracetamol-induced antidepressant-like and anticompulsive effects may, at least partially, involve both the serotonergic and the endocannabinoid system. In addition, coadministration of paracetamol and fluoxetine/AM404 at subeffective doses produced synergistic effects, indicating that subthreshold doses of fluoxetine and paracetamol may enable better management in depression and obsessive-compulsive disorder comorbid patients.

Fluoxetine ameliorates behavioral and neuropathological deficits in a transgenic model mouse of α-synucleinopathy.

PubMed

Ubhi, Kiren; Inglis, Chandra; Mante, Michael; Patrick, Christina; Adame, Anthony; Spencer, Brian; Rockenstein, Edward; May, Verena; Winkler, Juergen; Masliah, Eliezer

2012-04-01

The term α-synucleinopathies refers to a group of age-related neurological disorders including Parkinson's disease (PD), Dementia with Lewy Bodies (DLB) and Multiple System Atrophy (MSA) that display an abnormal accumulation of alpha-synuclein (α-syn). In contrast to the neuronal α-syn accumulation observed in PD and DLB, MSA is characterized by a widespread oligodendrocytic α-syn accumulation. Transgenic mice expressing human α-syn under the oligodendrocyte-specific myelin basic protein promoter (MBP1-hαsyn tg mice) model many of the behavioral and neuropathological alterations observed in MSA. Fluoxetine, a selective serotonin reuptake inhibitor, has been shown to be protective in toxin-induced models of PD, however its effects in an in vivo transgenic model of α-synucleinopathy remain unclear. In this context, this study examined the effect of fluoxetine in the MBP1-hαsyn tg mice, a model of MSA. Fluoxetine administration ameliorated motor deficits in the MBP1-hαsyn tg mice, with a concomitant decrease in neurodegenerative pathology in the basal ganglia, neocortex and hippocampus. Fluoxetine administration also increased levels of the neurotrophic factors, GDNF (glial-derived neurotrophic factor) and BDNF (brain-derived neurotrophic factor) in the MBP1-hαsyn tg mice compared to vehicle-treated tg mice. This fluoxetine-induced increase in GDNF and BDNF protein levels was accompanied by activation of the ERK signaling pathway. The effects of fluoxetine administration on myelin and serotonin markers were also examined. Collectively these results indicate that fluoxetine may represent a novel therapeutic intervention for MSA and other neurodegenerative disorders. Copyright Â© 2011 Elsevier Inc. All rights reserved.
Acute treatment of migraine headaches.

PubMed

Taylor, Frederick R

2010-04-01

Optimum acute treatment of migraine requires prevention of headache as a top priority. Recognition of the multitude of migraine presentations, the frequency of total headache attacks, and number of days of headache disability are critical. Successful treatment requires excellent patient-clinician communication enhancing confidence and mutual trust based on patient needs and preferences. Optimum management of acute migraine nearly always requires pharmacologic treatment for rapid resolution. Migraine-specific triptans, dihydroergotamine, and several antiinflammatories have substantial empirical clinical efficacy. Older nonspecific drugs, particularly butalbital and opioids, contribute to medication overuse headache and are to be avoided. Clinicians should utilize evidence-based acute migraine-specific therapy stressing the imperative acute treatment goal of early intervention, but not too often with the correct drug, formulation, and dose. This therapy needs to provide cost-effective fast results, meaningful to the patient while minimizing the need for additional drugs. Migraine-ACT evaluates 2-hour pain freedom with return to normal function, comfort with treatment, and consistency of response. Employ a thoroughly educated patient, formulary, testimonials, stratification, and rational cotherapy against the race to central sensitization for optimum outcomes. Thieme Medical Publishers.
Olive oil and leaf extract prevent fluoxetine-induced hepatotoxicity by attenuating oxidative stress, inflammation and apoptosis.

PubMed

Elgebaly, Hassan A; Mosa, Nermeen M; Allach, Mariam; El-Massry, Khaled F; El-Ghorab, Ahmed H; Al Hroob, Amir M; Mahmoud, Ayman M

2018-02-01

Olive oil and leaf extract have several health benefits; however, their beneficial effect against fluoxetine-induced liver injury has not been investigated. The present study aimed to scrutinize the impact of fluoxetine on the liver of rats and to evaluate the protective effects of olive oil and leaf extract. Rats received fluoxetine orally at dose of 10 mg/kg body weight for 7 consecutive days. The fluoxetine-induced rats were concurrently treated with olive oil or leaf extract. At the end of the experiment, blood and liver samples were collected for analysis. Fluoxetine administration significantly increased circulating ALT, AST, ALP and the pro-inflammatory cytokines TNF-α and IL-1β levels in rats. Histological analysis showed several alterations, such as inflammatory cells infiltration, hepatocyte vacuolation and dilated sinusoids in the liver of fluoxetine-induced rats. Concurrent supplementation of olive oil and olive leaf extract significantly reduced circulating liver function marker enzymes and pro-inflammatory cytokines, and prevented fluoxetine-induced histological alterations. Both olive oil and leaf extract significantly decreased liver lipid peroxidation and nitric oxide, and ameliorated liver glutathione, superoxide dismutase, catalase and glutathione peroxidase. In addition, olive oil and leaf extract prevented fluoxetine-induced apoptosis in the liver of rats as evidenced by decreased expression of Bax and caspase-3, and up-regulated expression of Bcl-2. In conclusion, olive oil and leaf extract protect against ﬂuoxetine-induced liver injury in rats through attenuation of oxidative stress, inflammation and apoptosis. Copyright © 2017 Elsevier Masson SAS. All rights reserved.
Interleukin-1β causes fluoxetine resistance in an animal model of epilepsy-associated depression.

PubMed

Pineda, Eduardo A; Hensler, Julie G; Sankar, Raman; Shin, Don; Burke, Teresa F; Mazarati, Andréy M

2012-04-01

Depression represents a common comorbidity of epilepsy and is frequently resistant to selective serotonin reuptake inhibitors (SSRI). We tested the hypothesis that the SSRI resistance in epilepsy associated depression may be a result of a pathologically enhanced interleukin-1β (IL1-β) signaling, and consequently that the blockade of IL1-β may restore the effectiveness of SSRI. Epilepsy and concurrent depression-like impairments were induced in Wistar rats by pilocarpine status epilepticus (SE). The effects of the 2-week long treatment with fluoxetine, interleukin-1 receptor antagonist (IL-1ra), and their combination were examined using behavioral, biochemical, neuroendocrine, and autoradiographic assays. In post-SE rats, depression-like impairments included behavioral deficits indicative of hopelessness and anhedonia; the hyperactivity of the hypothalamo-pituitary-adrenocortical axis; the diminished serotonin output from raphe nucleus; and the upregulation of presynaptic serotonin 1-A (5-HT1A) receptors. Fluoxetine monotherapy exerted no antidepressant effects, whereas the treatment with IL-1ra led to the complete reversal of anhedonia and to a partial improvement of all other depressive impairments. Combined administration of fluoxetine and IL-1ra completely abolished all hallmarks of epilepsy-associated depressive abnormalities, with the exception of the hyperactivity of the hypothalamo-pituitary-adrenocortical axis, the latter remaining only partially improved. We propose that in certain forms of depression, including but not limited to depression associated with epilepsy, the resistance to SSRI may be driven by the pathologically enhanced interleukin-1β signaling and by the subsequent upregulation of presynaptic 5-HT1A receptors. In such forms of depression, the use of interleukin-1β blockers in conjunction with SSRI may represent an effective therapeutic approach.
Fluoxetine Increases Hippocampal Neurogenesis and Induces Epigenetic Factors But Does Not Improve Functional Recovery after Traumatic Brain Injury

PubMed Central

Wang, Yonggang; Neumann, Melanie; Hansen, Katharina; Hong, Shuwhey M.; Kim, Sharon; Noble-Haeusslein, Linda J.

2011-01-01

Abstract The selective serotonin reuptake inhibitor fluoxetine induces hippocampal neurogenesis, stimulates maturation and synaptic plasticity of adult hippocampal neurons, and reduces motor/sensory and memory impairments in several CNS disorders. In the setting of traumatic brain injury (TBI), its effects on neuroplasticity and function have yet to be thoroughly investigated. Here we examined the efficacy of fluoxetine after a moderate to severe TBI, produced by a controlled cortical impact. Three days after TBI or sham surgery, mice were treated with fluoxetine (10 mg/kg/d) or vehicle for 4 weeks. To evaluate the effects of fluoxetine on neuroplasticity, hippocampal neurogenesis and epigenetic modification were studied. Stereologic analysis of the dentate gyrus revealed a significant increase in doublecortin-positive cells in brain-injured animals treated with fluoxetine relative to controls, a finding consistent with enhanced hippocampal neurogenesis. Epigenetic modifications, including an increase in histone 3 acetylation and induction of methyl-CpG-binding protein, a transcription factor involved in DNA methylation, were likewise seen by immunohistochemistry and quantitative Western immunoblots, respectively, in brain-injured animals treated with fluoxetine. To determine if fluoxetine improves neurological outcomes after TBI, gait function and spatial learning and memory were assessed by the CatWalk-assisted gait test and Barnes maze test, respectively. No differences in these parameters were seen between fluoxetine- and vehicle-treated animals. Thus while fluoxetine enhanced neuroplasticity in the hippocampus after TBI, its chronic administration did not restore locomotor function or ameliorate memory deficits. PMID:21175261
Effects of periadolescent fluoxetine and paroxetine on elevated plus-maze, acoustic startle, and swimming immobility in rats while on and off-drug.

PubMed

Vorhees, Charles V; Morford, LaRonda R; Graham, Devon L; Skelton, Matthew R; Williams, Michael T

2011-10-05

Whether selective serotonin reuptake inhibitors (SSRIs) exposure during adolescent brain development causes lasting effects remains unresolved. Assess the effects of fluoxetine and paroxetine 60 days after adolescent exposure compared with when on-drug. Male Sprague-Dawley littermates (41 litters) were gavaged on postnatal days 33-53 with fluoxetine (3 or 10 mg/kg/day), paroxetine (3, 10 or, 17 mg/kg/day), or water; half were tested while on-drug (21 litters) and half after 60 days off-drug (20 litters). The highest dose of the drugs reduced body weight gain during treatment that rebounded 1 week post-treatment. On-drug, no significant group differences were found on elevated plus maze time-in-open, zone entries, or latency to first open entry; however, the high dose of paroxetine significantly reduced head-dips (N=20/group). No significant effects were found on-drug for acoustic startle response/prepulse inhibition (ASR/PPI) although a trend (p<0.10) was seen, which after combining dose levels, showed a significant increase in ASR amplitude for both fluoxetine and paroxetine (N=20-21/group). No differences on immobility time were seen in the Porsolt forced swim test or in plasma corticosterone at the end of forced swim (N-19-21/group). Off-drug, no effects were seen in the elevated plus maze (N=16/group), ASR/PPI (N=20/group), forced swim (N=19-20/group), or plasma corticosterone (N=19/group). At the doses tested, fluoxetine and paroxetine induced minor effects with drug on-board but no residual, long-term adverse effects in rats 60 days after drug discontinuation. The data provide no evidence that fluoxetine or paroxetine have long-term adverse effects on the behaviors measured here after adolescent to young adult exposure.
Extreme Response Style in Recurrent and Chronically Depressed Patients: Change with Antidepressant Administration and Stability during Continuation Treatment

ERIC Educational Resources Information Center

Peterson, Timothy J.; Feldman, Greg; Harley, Rebecca; Fresco, David M.; Graves, Lesley; Holmes, Avram; Bogdan, Ryan; Papakostas, George I.; Bohn, Laurie; Lury, R. Alana; Fava, Maurizio; Segal, Zindel V.

2007-01-01

The authors examined extreme response style in recurrently and chronically depressed patients, assessing its role in therapeutic outcome. During the acute phase, outpatients with major depressive disorder (N = 384) were treated with fluoxetine for 8 weeks. Remitted patients (n = 132) entered a continuation phase during which their fluoxetine dose…
Treatment Option Overview (Adult Acute Lymphoblastic Leukemia)

MedlinePlus

... Childhood ALL Treatment Childhood AML Treatment Research Adult Acute Lymphoblastic Leukemia Treatment (PDQ®)–Patient Version General Information About Adult Acute Lymphoblastic Leukemia Go to Health Professional Version Key ...
Treatment Options for Adult Acute Lymphoblastic Leukemia

MedlinePlus

... Childhood ALL Treatment Childhood AML Treatment Research Adult Acute Lymphoblastic Leukemia Treatment (PDQ®)–Patient Version General Information About Adult Acute Lymphoblastic Leukemia Go to Health Professional Version Key ...
An Examination of Fluoxetine for the Treatment of Selective Mutism Using a Nonconcurrent Multiple-Baseline Single-Case Design Across 5 Cases.

PubMed

Barterian, Justin A; Sanchez, Joel M; Magen, Jed; Siroky, Allison K; Mash, Brittany L; Carlson, John S

2018-01-01

This study examined the utility of fluoxetine in the treatment of 5 children, aged 5 to 14 years, diagnosed with selective mutism who also demonstrated symptoms of social anxiety. A nonconcurrent, randomized, multiple-baseline, single-case design with a single-blind placebo-controlled procedure was used. Parents and the study psychiatrist completed multiple methods of assessment including Direct Behavior Ratings and questionnaires. Treatment outcomes were evaluated by calculating effect sizes for each participant as an individual and for the participants as a group. Information regarding adverse effects with an emphasis on behavioral disinhibition and ratings of parental acceptance of the intervention was gathered. All 5 children experienced improvement in social anxiety, responsive speech, and spontaneous speech with medium to large effect sizes; however, children still met criteria for selective mutism at the end of the study. Adverse events were minimal, with only 2 children experiencing brief occurrences of minor behavioral disinhibition. Parents found the treatment highly acceptable.
Plasma fluoxetine concentrations and clinical improvement in an adolescent sample diagnosed with major depressive disorder, obsessive-compulsive disorder, or generalized anxiety disorder.

PubMed

Blázquez, Ana; Mas, Sergi; Plana, Maria Teresa; Gassó, Patricia; Méndez, Iria; Torra, Mercè; Arnaiz, Joan Albert; Lafuente, Amàlia; Lázaro, Luisa

2014-06-01

Fluoxetine (FLX) has been one of the most widely studied selective serotonin reuptake inhibitors in adolescents. Despite its efficacy, however, 30% to 40% of patients do not respond to treatment. The aim of this study was to evaluate whether clinical improvement or adverse events are related to the corrected dose of FLX at 8 and 12 weeks after starting treatment in a sample of adolescents diagnosed with major depressive disorder, obsessive-compulsive disorder, or generalized anxiety disorder. Seventy-four subjects aged between 10 and 17 years participated in the study. Clinical improvement was measured with the Clinical Global Impression-Improvement Scale, whereas the UKU (Udvalg for Klinske Undersogelser) scale was administered to assess adverse effects of treatment. Fluoxetine per kilograms of body weight was related to serum concentration of FLX, NORFLX (norfluoxetine), FLX + NORFLX, and FLX/NORFLX. No relationship was found between dose-corrected FLX levels and therapeutic or adverse effects. No differences in serum concentrations were found between responders and nonresponders to treatment. Sex differences were observed in relation to dose and FLX serum concentration. The analysis by diagnosis revealed differences in FLX dose between obsessive-compulsive disorder patients and both generalized anxiety disorder and major depressive disorder patients. Fluoxetine response seems to be influenced by factors such as sex, diagnosis, or certain genes that might be involved in the drug's pharmacokinetics and pharmacodynamics. Clinical and pharmacogenetic studies are needed to elucidate further the differences between treatment responders and nonresponders.
Effects of fluoxetine on fine motor performance in dysthymia: an 8-week, nonrandomized, open-label study.

PubMed

Schrijvers, Didier; Maas, Yvonne J; Sabbe, Bernard G C

2009-01-01

Present findings on psychomotor retardation in dysthymia are inconsistent and changes in psychomotor performance during antidepressant treatment have not been investigated in this population to date. The present study aims to explore the psychomotor effects of an 8-week regimen of fluoxetine in dysthymic patients. Dysthymic patients (both inpatients and outpatients of the Psychiatric Hospital Sint-Norbertus, Duffel, Belgium), presenting over a period of 2 years, meeting the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision criteria for dysthymia, and having Hamilton Depression Rating Scale scores of > or = 12 were enrolled. During 8 weeks of treatment with fluoxetine 20 mg/d, depression severity and graphic motor activity were assessed 4 times by recording the time (a reaction time [RT] and a movement time [MT]) participants needed to copy single lines and simple and complex figures. The patients' outcomes were compared with those of untreated, healthy controls, matched for sex and comparable age and education. The assessors were masked to treatment and group. Eighteen dysthymic patients (mean age, 40 years; male/female ratio, 4/14; mean weight, 70 kg; all white) were treated; 18 healthy controls (mean age, 40 years; male/female ratio, 4/14; mean weight, 72 kg; all white) were used as comparison. The overall patient group experienced significant psychomotor changes only in association with the complex figure-copying task (RT: F = 5.67, P < 0.05). In a subgroup analysis of 9 patients who clinically responded to treatment (ie, > 40% decrease in severity scores), significant improvements were observed only for the RT of the line- (F = 4.75, P < 0.05) and complex figure-copying task (F = 11.86, P < 0.01) and the MT of the simple figure-copying task (F = 7.57, P < 0.05), but not for the other psychomotor variables. Although some significant psychomotor changes were observed in a subgroup of clinically responsive dysthymic patients, the
Fluoxetine potentiates methylphenidate-induced gene regulation in addiction-related brain regions: Concerns for use of cognitive enhancers?

PubMed Central

Steiner, Heinz; Van Waes, Vincent; Marinelli, Michela

2009-01-01

Background There is growing use of psychostimulant cognitive enhancers such as methylphenidate (Ritalin). Methylphenidate differs from the psychostimulant cocaine because it does not enhance brain levels of serotonin. We investigated whether exposure to methylphenidate combined with a serotonin-enhancing medication, the prototypical selective serotonin reuptake inhibitor (SSRI) fluoxetine (Prozac), would produce more “cocaine-like” molecular and behavioral changes. Methods We measured the effects of fluoxetine on gene expression induced by the cognitive enhancer methylphenidate in the striatum and nucleus accumbens of rats, by in situ hybridization histochemistry. We also determined whether fluoxetine modified behavioral effects of methylphenidate. Results Fluoxetine robustly potentiated methylphenidate-induced expression of the transcription factors c-fos and zif 268 throughout the striatum and to some degree in the nucleus accumbens. Fluoxetine also enhanced methylphenidate-induced stereotypical behavior. Conclusions Both potentiated gene regulation in the striatum and the behavioral effects indicate that combining the SSRI fluoxetine with the cognitive enhancer methylphenidate mimics cocaine effects, consistent with an increased risk for substance use disorder. PMID:19931852
Bioconcentration of the antidepressant fluoxetine and its effects on the physiological and biochemical status in Daphnia magna.

PubMed

Ding, Jiannan; Zou, Hua; Liu, Qingqing; Zhang, Shanshan; Mamitiana Razanajatovo, Roger

2017-08-01

The aim of this study was to evaluate the bioconcentration potential of fluoxetine and its biological effects in Daphnia magna. After 48h of waterborne exposure, the bioconcentration of fluoxetine in D. magna was determined to be 460.61 and 174.41Lkg -1 for nominal exposure concentrations of 0.5 and 5µgL -1 , respectively. Moreover, various biological endpoints, including physiological responses (filtration and ingestion rates), enzymatic biomarkers related to neurotoxicity [acetylcholinesterase (AChE)] and antioxidant defense [superoxide dismutase (SOD)], and an oxidative stress damage marker [malondialdehyde (MDA)], were assessed. Fluoxetine exposure increased the filtration rate of daphnia, while the ingestion rate was not obviously modified. AChE activity was significantly inhibited, highlighting the neurotoxicity of fluoxetine on D. magna. However, with some alterations in the SOD activity and MDA content, no obvious oxidative damage was observed in D. magna exposed to fluoxetine at the tested concentrations. These results indicate that fluoxetine can be accumulated and consequently induce physiological and biochemical perturbations in D. magna. Copyright © 2017. Published by Elsevier Inc.
Emergence of anxiety-like behaviours in depressive-like Cpe(fat/fat) mice.

PubMed

Rodriguiz, Ramona M; Wilkins, John J; Creson, Thomas K; Biswas, Reeta; Berezniuk, Iryna; Fricker, Arun D; Fricker, Lloyd D; Wetsel, William C

2013-08-01

Cpe(fat/fat) mice have a point mutation in carboxypeptidase E (Cpe), an exopeptidase that removes C-terminal basic amino acids from intermediates to produce bioactive peptides. The mutation renders the enzyme inactive and unstable. The absence of Cpe activity in these mutants leads to abnormal processing of many peptides, with elevated levels of intermediates and greatly reduced levels of the mature peptides. Cpe(fat/fat) mice develop obesity, diabetes and infertility in adulthood. We examined whether anxiety- and/or depressive-like behaviours are also present. Anxiety-like responses are not evident in young Cpe(fat/fat) mice (∼60 d), but appear in older animals (>90 d). These behaviours are reversed by acute treatment with diazepam or fluoxetine. In contrast, increased immobilities in forced swim and tail suspension are evident in all age groups examined. These behaviours are reversed by acute administration of reboxetine. In comparison acute treatments with fluoxetine or bupropion are ineffective; however, immobility times are normalized with 2 wk treatment. These data demonstrate that Cpe(fat/fat) mice display depressive-like responses aged ∼60 d, whereas anxiety-like behaviours emerge ∼1 month later. In tail suspension, the reboxetine findings show that noradrenergic actions of antidepressants are intact in Cpe(fat/fat) mice. The ability of acute fluoxetine treatment to rescue anxiety-like while leaving depressive-like responses unaffected suggests that serotonin mechanisms underlying these behaviours are different. Since depressive-like responses in the Cpe(fat/fat) mice are rescued by 2 wk, but not acute, treatment with fluoxetine or bupropion, these mice may serve as a useful model that resembles human depression.
The antidepressant effect of melatonin and fluoxetine in diabetic rats is associated with a reduction of the oxidative stress in the prefrontal and hippocampal cortices.

PubMed

Rebai, Redouane; Jasmin, Luc; Boudah, Abdennacer

2017-09-01

In the past few years possible mechanisms that link diabetes and depression have been found. One of these mechanisms is the increase in lipid peroxidation and decrease in antioxidant activity in the hippocampal and prefrontal cortices, which are brain areas involved in mood. The goal of the present study was to evaluate the effect of an antidepressant and of an antioxidant on behavior and oxidative activity in brains of diabetic rats. Rats rendered diabetic after a treatment with streptozotocin (STZ) (60mg/kg) were treated with fluoxetine (15mg/kg), melatonin (10mg/kg), or vehicle for 4 weeks. All animals were tested for signs of depression and anxiety using the elevated plus maze (EPM), open field test (OFT) and the forced swim test (FST). Four groups were compared: (1) normoglycemic, (2) hyperglycemic vehicle treated, and hyperglycemic (3) fluoxetine or (4) melatonin treated rats. On the last day of the study, blood samples were obtained to determine the levels of hemoglobin A1c (HbA1c). Also, brain samples were collected to measure the oxidative stress in the hippocampal and prefrontal cortices using the thiobarbituric acid reactive substances (TBARS) assay. The activity of the antioxidant enzymes catalase (CAT), glutathione peroxidase (GPx), and glutathione S-transferase (GST) were also measured on the brain samples. The results show that both fluoxetine and melatonin decrease the signs of depression and anxiety in all tests. Concomitantly, the levels of HbA1c were reduced in drug treated rats, and to a greater degree in the fluoxetine group. In the cerebral cortex of diabetic rats, TBARS was increased, while the activity of CAT, GPx and GST were decreased. Fluoxetine and melatonin treatments decreased TBARS in both cortices. In the prefrontal cortex, fluoxetine and melatonin restored the activity of CAT, while only melatonin improved the activity of GPx and GST. In the hippocampus, the activity of GPx alone was restored by melatonin, while fluoxetine had no
Regional-specific effect of fluoxetine on rapidly dividing progenitors along the dorsoventral axis of the hippocampus.

PubMed

Zhou, Qi-Gang; Lee, Daehoon; Ro, Eun Jeoung; Suh, Hoonkyo

2016-10-19

Hippocampus-dependent cognitive and emotional function appears to be regionally dissociated along the dorsoventral (DV) axis of the hippocampus. Recent observations that adult hippocampal neurogenesis plays a critical role in both cognition and emotion raised an interesting question whether adult neurogenesis within specific subregions of the hippocampus contributes to these distinct functions. We examined the regional-specific and cell type-specific effects of fluoxetine, which requires adult hippocampal neurogenesis to function as an antidepressant, on the proliferation of hippocampal neural stem cells (NSCs). Fluoxetine specifically increased proliferation of NSCs located in the ventral region of the hippocampus while the mitotic index of NSCs in the dorsal portion of the hippocampus remained unaltered. Moreover, within the ventral hippocampus, type II NSC and neuroblast populations specifically responded to fluoxetine, showing increased proliferation; however, proliferation of type I NSCs was unchanged in response to fluoxetine. Activation or inhibition of serotonin receptor 1A (5-HTR1A) recapitulated or abolished the effect of fluoxetine on proliferation of type II NSCs and neuroblast populations in the ventral hippocampus. Our study showed that the effect of fluoxetine on proliferation is dependent upon the type and the position of the NSCs along the DV axis of the hippocampus.
Benefits from antidepressants: synthesis of 6-week patient-level outcomes from double-blind placebo-controlled randomized trials of fluoxetine and venlafaxine.

PubMed

Gibbons, Robert D; Hur, Kwan; Brown, C Hendricks; Davis, John M; Mann, J John

2012-06-01

Some meta-analyses suggest that efficacy of antidepressants for major depression is overstated and limited to severe depression. To determine the short-term efficacy of antidepressants for treating major depressive disorder in youth, adult, and geriatric populations. Reanalysis of all intent-to-treat person-level longitudinal data during the first 6 weeks of treatment of major depressive disorder from 12 adult, 4 geriatric, and 4 youth randomized controlled trials of fluoxetine hydrochloride and 21 adult trials of venlafaxine hydrochloride. All sponsor-conducted randomized controlled trials of fluoxetine and venlafaxine. Children's Depression Rating Scale-Revised scores (youth population), Hamilton Depression Rating Scale scores (adult and geriatric populations), and estimated response and remission rates at 6 weeks were analyzed for 2635 adults, 960 geriatric patients, and 708 youths receiving fluoxetine and for 2421 adults receiving immediate-release venlafaxine and 2461 adults receiving extended-release venlafaxine. Patients in all age and drug groups had significantly greater improvement relative to control patients receiving placebo. The differential rate of improvement was largest for adults receiving fluoxetine (34.6% greater than those receiving placebo). Youths had the largest treated vs control difference in response rates (24.1%) and remission rates (30.1%), with adult differences generally in the 15.6% (remission) to 21.4% (response) range. Geriatric patients had the smallest drug-placebo differences, an 18.5% greater rate of improvement, 9.9% for response and 6.5% for remission. Immediate-release venlafaxine produced larger effects than extended-release venlafaxine. Baseline severity could not be shown to affect symptom reduction. To our knowledge, this is the first research synthesis in this area to use complete longitudinal person-level data from a large set of published and unpublished studies. The results do not support previous findings that
Effect of desipramine and fluoxetine on energy metabolism of cerebral mitochondria.

PubMed

Villa, Roberto Federico; Ferrari, Federica; Gorini, Antonella; Brunello, Nicoletta; Tascedda, Fabio

2016-08-25

Brain bioenergetic abnormalities in mood disorders were detected by neuroimaging in vivo studies in humans. Because of the increasing importance of mitochondrial pathogenetic hypothesis of Depression, in this study the effects of sub-chronic treatment (21days) with desipramine (15mg/kg) and fluoxetine (10mg/kg) were evaluated on brain energy metabolism. On mitochondria in vivo located in neuronal soma (somatic) and on mitochondria of synapses (synaptic), the catalytic activities of regulatory enzymes of mitochondrial energy-yielding metabolic pathways were assayed. Antidepressants in vivo treatment modified the activities of selected enzymes of different mitochondria, leading to metabolic modifications in the energy metabolism of brain cortex: (a) the enhancement of cytochrome oxidase activity on somatic mitochondria; (b) the decrease of malate, succinate dehydrogenase and glutamate-pyruvate transaminase activities of synaptic mitochondria; (c) the selective effect of fluoxetine on enzymes related to glutamate metabolism. These results overcome the conflicting data so far obtained with antidepressants on brain energy metabolism, because the enzymatic analyses were made on mitochondria with diversified neuronal in vivo localization, i.e. on somatic and synaptic. This research is the first investigation on the pharmacodynamics of antidepressants studied at subcellular level, in the perspective of (i) assessing the role of energy metabolism of cerebral mitochondria in animal models of mood disorders, and (ii) highlighting new therapeutical strategies for antidepressants targeting brain bioenergetics. Copyright © 2016 IBRO. Published by Elsevier Ltd. All rights reserved.
Effects of co-administration of fluoxetine or tianeptine with metyrapone on immobility time and plasma corticosterone concentration in rats subjected to the forced swim test.

PubMed

Rogóz, Zofia; Skuza, Grazyna; Leśkiewicz, Monika; Budziszewska, Bogusława

2008-01-01

Major depression is frequently associated with hyperactivity of the hypothalamic-pituitary-adrenocortical axis, and glucocorticoid synthesis inhibitors have been shown to exert antidepressant action. The aim of the present study was to examine the effect of co-administration of fluoxetine or tianeptine with metyrapone on immobility time and plasma corticosterone concentration in male Wistar rats subjected to the forced swim test. Metyrapone alone (50 mg/kg, but not 25 mg/kg) reduced the immobility time of rats in the forced swim test; moreover, both doses tested (25 and 50 mg/kg), dose-dependently decreased the stress-induced plasma corticosterone concentration. Joint administration of fluoxetine or tianeptine (10 mg/kg) and metyrapone (25 mg/kg - a dose inactive per se) exhibited antidepressant-like activity in the forced swim test in rats. WAY 100636 (a 5-HT(1A) antagonist), but not prazosin (an alpha(1)-adrenergic antagonist), used in doses ineffective in the forced swim test, inhibited the antidepressant-like effect induced by co-administration of fluoxetine or tianeptine with metyrapone (25 mg/kg). Combined treatment of fluoxetine or tianeptine and metyrapone inhibited stress-induced corticosterone secretion to a similar extent as metyrapone alone. The obtained results indicate that metyrapone potentiates the antidepressant-like activity of fluoxetine or tianeptine and that, among other mechanisms, 5-HT(1A) receptors may play some role in this effect. Moreover, metyrapone exerts a beneficial effect on the stress-induced increase in plasma corticosterone concentration. These findings suggest that the co-administration of metyrapone and an antidepressant drug may be useful for the treatment of drug-resistant depression and/or depression associated with a high cortisol level.

Fluoxetine Monotherapy in Attention-Deficit/Hyperactivity Disorder and Comorbid Non-Bipolar Mood Disorders in Children and Adolescents

ERIC Educational Resources Information Center

Quintana, Humberto; Butterbaugh, Grant J.; Purnell, William; Layman, Ann K.

2007-01-01

Children with attention-deficit/hyperactivity disorder (ADHD) are at increased risk for developing comorbid non-bipolar mood disorders. Fluoxetine monotherapy is an established treatment for pediatric mood disorders; however its efficacy in ADHD and comorbid mood disorder is unknown. Therefore, we evaluated 30 children who met DSM-IV criteria for…
Anxiogenic-like effects of fluoxetine render adult male rats vulnerable to the effects of a novel stress.

PubMed

Gomez, Francisca; García-García, Luis

2017-02-01

Fluoxetine (FLX) has paradoxical anxiogenic-like effects during the acute phase of treatment. In adolescent (35d-old) male rats, the stress-like effects induced by short-term (3d-4d) FLX treatment appear to involve up-regulation of paraventricular nucleus (PVN) arginine vasopressin (AVP) mRNA. However, studies on FLX-induced anxiety-like effects in adult rodents are inconclusive. Herein, we sought to study the response of adult male rats (60-65d-old) to a similar FLX treatment, also investigating how the stressful component, inherent to our experimental conditions, contributed to the responses. We show that FLX acutely increased plasma corticosterone concentrations while it attenuated the stress-induced-hyperthermia (SIH) as well as it reduced (≈40%) basal POMC mRNA expression in the arcuate nucleus (ARC). However, FLX did not alter the basal expression of PVN-corticotrophin-releasing hormone (CRH), anterior pituitary-pro-opiomelanocortin (POMC) and raphe nucleusserotonin transporter (SERT). Nonetheless, some regressions point towards the plausibility that FLX activated the hypothalamic-pituitary-adrenal (HPA). The behavioral study revealed that FLX acutely increased emotional reactivity in the holeboard, effect followed by a body weight loss of ≈2.5% after 24h. Interestingly, i.p. injection with vehicle did not have behavioral effects, furthermore, after experiencing the stressful component of the holeboard, the rats kept eating and gaining weight as normal. By contrast, the stress-naïve rats reduced food intake and gained less weight although maintaining a positive energy state. Therefore, on one hand, repetition of a mild stressor would unchain compensatory mechanisms to restore energy homeostasis after stress increasing the resiliency to novel stressors. On the other hand, FLX might render stressed adult rats vulnerable to novel stressors through the emergence of counter-regulatory changes, involving HPA axis activation and diminished sympathetic output
Fluoxetine (Prozac) Binding to Serotonin Transporter Is Modulated by Chloride and Conformational Changes

PubMed Central

Tavoulari, Sotiria; Forrest, Lucy R.; Rudnick, Gary

2010-01-01

Serotonin transporter (SERT) is the main target for widely used antidepressant agents. Several of these drugs, including imipramine, citalopram, sertraline, and fluoxetine (Prozac), bound more avidly to SERT in the presence of Cl–. In contrast, Cl– did not enhance cocaine or paroxetine binding. A Cl– binding site recently identified in SERT, and shown to be important for Cl– dependent transport, was also critical for the Cl– dependence of antidepressant affinity. Mutation of the residues contributing to this site eliminated the Cl–-mediated affinity increase for imipramine and fluoxetine. Analysis of ligand docking to a single state of SERT indicated only small differences in the energy of interaction between bound ligands and Cl–. These differences in interaction energy cannot account for the affinity differences observed for Cl– dependence. However, fluoxetine binding led to a conformational change, detected by cysteine accessibility experiments, that was qualitatively different from that induced by cocaine or other ligands. Given the known Cl– requirement for serotonin-induced conformational changes, we propose that Cl– binding facilitates conformational changes required for optimal binding of fluoxetine and other antidepressant drugs. PMID:19641126
Enantiomeric separation of fluoxetine and norfluoxetine in plasma and serum samples with high detection sensitivity capillary electrophoresis.

PubMed

Desiderio, C; Rudaz, S; Raggi, M A; Fanali, S

1999-11-01

A capillary electrophoresis method was optimized for the stereoselective analysis of the antidepressant drug fluoxetine and its main demethylated metabolite norfluoxetine using a cyclodextrin-modified sodium phosphate buffer at pH 2.5. The combination of a neutral and a negatively charged cyclodextrin, dimethylated-beta- and phosphated-gamma-respectively, provided the baseline enantiomeric separation of the two compounds. The very low concentrations of chiral selectors employed together with the use of a high sensitivity detection cell of special design (zeta-shaped) in a diode array UV detector allowed us to reach a limit of detection of 0.005 and 0.01 microg/mL for fluoxetine and norfluoxetine, respectively. Analysis of fluoxetine and norfluoxetine standard mixtures showed a reproducibility of migration times and peak area and linearity in the concentration range of 0.1-2.0 microg/mL. The optimized method was applied to the analysis of clinical serum and plasma samples of patients under depression therapy. In all the analyzed samples the enantiomeric forms of fluoxetine and norfluoxetine were easily identified. The fluoxetine and metabolite enantiomeric ratio confirmed the stereoselectivity of the metabolic process of the fluoxetine drug in accordance with the literature data.
Impacts of the antidepressant fluoxetine on the anti-predator behaviours of wild guppies (Poecilia reticulata).

PubMed

Saaristo, Minna; McLennan, Alisha; Johnstone, Christopher P; Clarke, Bradley O; Wong, Bob B M

2017-02-01

Chemical pollution from pharmaceuticals is increasingly recognised as a major threat to aquatic communities. One compound of great concern is fluoxetine, which is one of the most widely prescribed psychoactive drugs in the world and frequently detected in the environment. The aim of this study was to investigate the effects of 28-d fluoxetine exposure at two environmentally relevant levels (measured concentrations: 4ng/L and 16ng/L) on anti-predator behaviour in wild guppies (Poecilia reticulata). This was achieved by subjecting fluoxetine-exposed and unexposed guppies to a simulated bird strike and recording their subsequent behavioural responses. We found that exposure to fluoxetine affected the anti-predator behaviour of guppies, with exposed fish remaining stationary for longer (i.e. 'freezing' behaviour) after the simulated strike and also spending more time under plant cover. By contrast, control fish were significantly more active and explored the tank more, as indicated by the distance covered per minute over the period fish spent swimming. Furthermore, behavioural shifts were sex-dependent, with evidence of a non-monotonic dose-response among the fluoxetine-exposed fish. This is one of the first studies to show that exposure to environmentally relevant concentrations of fluoxetine can alter the anti-predator behaviour of adult fish. In addition to the obvious repercussions for survival, impaired anti-predator behaviour can have direct impacts on fitness and influence the overall population dynamics of species. Copyright © 2016 Elsevier B.V. All rights reserved.
Effects of moderate treadmill exercise and fluoxetine on behavioural and cognitive deficits, hypothalamic-pituitary-adrenal axis dysfunction and alternations in hippocampal BDNF and mRNA expression of apoptosis - related proteins in a rat model of post-traumatic stress disorder.

PubMed

Shafia, Sakineh; Vafaei, Abbas Ali; Samaei, Seyed Afshin; Bandegi, Ahmad Reza; Rafiei, Alireza; Valadan, Reza; Hosseini-Khah, Zahra; Mohammadkhani, Raziyeh; Rashidy-Pour, Ali

2017-03-01

Post-traumatic stress disorder (PTSD) is a condition that develops after an individual has experienced a major trauma. Currently, selective serotonin reuptake inhibitors (SSRIs) like fluoxetine are the first-line choice in PTSD drug treatment but their moderate response rates and side effects indicate an urgent need for the development of new treatment. Physical activity is known to improve symptoms of certain neuropsychiatric disorders. The present study investigated the effects of moderate treadmill exercise, the antidepressant fluoxetine and the combined treatment on behavioural deficits, and hypothalamic-pituitary-adrenal (HPA) axis dysfunction. We also examined alternations in hippocampal brain-derived neurotrophic factor (BDNF) and mRNA expression of apoptosis - related proteins in a rat model of PTSD: the single prolonged stress (SPS) model. Rats were exposed to SPS (restraint for 2h, forced swimming for 20min and ether anaesthesia) and were then kept undisturbed for 14days. After that, SPS rats were subjected to chronic treatment with fluoxetine (10mg/kg/day, for 4weeks), moderate treadmill running (4weeks, 5day per week) and the combined treatment (fluoxetine plus treadmill exercise), followed by behavioural, biochemical and apoptosis markers assessments. SPS rats exhibited increased anxiety levels in the elevated plus maze and light/dark box, impaired fear conditioning and extinction in inhibitory avoidance (IA) task, impaired spatial memory in a recognition location memory task and enhanced negative feedback on the HPA axis following a dexamethasone suppression test. SPS rats also showed reduced hippocampal BDNF and enhanced apoptosis. Moderate treadmill exercise, fluoxetine and the combined treatment alleviated the SPS-induced alterations in terms of anxiety levels, HPA axis inhibition, IA conditioning and extinction, hippocampal BDNF and apoptosis markers. Furthermore, the combined treatment was more effective than fluoxetine alone, but in most tests
Treatment of Acute Pelvic Inflammatory Disease

PubMed Central

Sweet, Richard L.

2011-01-01

Pelvic inflammatory disease (PID), one of the most common infections in nonpregnant women of reproductive age, remains an important public health problem. It is associated with major long-term sequelae, including tubal factor infertility, ectopic pregnancy, and chronic pelvic pain. In addition, treatment of acute PID and its complications incurs substantial health care costs. Prevention of these long-term sequelae is dependent upon development of treatment strategies based on knowledge of the microbiologic etiology of acute PID. It is well accepted that acute PID is a polymicrobic infection. The sexually transmitted organisms, Neisseria gonorrhoeae and Chlamydia trachomatis, are present in many cases, and microorganisms comprising the endogenous vaginal and cervical flora are frequently associated with PID. This includes anaerobic and facultative bacteria, similar to those associated with bacterial vaginosis. Genital tract mycoplasmas, most importantly Mycoplasma genitalium, have recently also been implicated as a cause of acute PID. As a consequence, treatment regimens for acute PID should provide broad spectrum coverage that is effective against these microorganisms. PMID:22228985
Fluoxetine and Norfluoxetine Revisited: New Insights into the Electrochemical and Spectroscopic Properties

NASA Astrophysics Data System (ADS)

Garrido, E. Manuela; Garrido, Jorge; Calheiros, Rita; Marques, M. Paula M.; Borges, Fernanda

2009-08-01

The extent to which humans and wildlife are exposed to the vast array of anthropogenic chemicals and their degradation products, along with related naturally occurring compounds, is nowadays an important issue. The study of the physical-chemical properties of the compounds and/or degradation products is an important subject because some of them are intrinsically related to its resistance to degradation and/or bioaccumulation. Accordingly, the study of the electrochemical behavior of the selective serotonin reuptake inhibitor fluoxetine and its main metabolite norfluoxetine was investigated. The identification of the oxidation processes was done via two fluoxetine analogues, 1-(benzyloxy)-4-(trifluoromethyl)benzene and N-methyl-3-phenylpropan-1-amine hydrochloride. The oxidative processes occurring in fluoxetine are pH-dependent and were ascribed to the chemical moieties present in the molecule: the secondary amine group and the substituted aromatic nucleus. To perform an unequivocal ascription, the structural preferences of the drug and metabolite were also determined, by Raman spectroscopy coupled to quantum mechanical calculations (at the DFT level). The analytical data obtained in this work will allow the development of a rapid and unequivocal spectroscopic procedure suitable for fluoxetine identification, as well as to distinguish between the drug and its main metabolite.
Study on the treatment of acute thallium poisoning.

PubMed

Zhang, Hong-Tao; Qiao, Bao-Ping; Liu, Bao-Ping; Zhao, Xian-Guo

2014-05-01

Acute thallium poisoning rarely occurs but is a serious and even fatal medical condition. Currently, patients with acute thallium poisoning are usually treated with Prussian blue and blood purification therapy. However, there are few studies about these treatments for acute thallium poisoning. Nine patients with acute thallium poisoning from 1 family were treated successfully with Prussian blue and different types of blood purification therapies and analyzed. Prussian blue combined with sequential hemodialysis, hemoperfusion and/or continuous veno-venous hemofiltration were effective for the treatment of patients with acute thallium poisoning, even after delayed diagnosis. Blood purification therapies help in the clearance of thallium in those with acute thallium poisoning. Prussian blue treatment may do the benefit during this process.
Epigenetic and genetic variants in the HTR1B gene and clinical improvement in children and adolescents treated with fluoxetine.

PubMed

Gassó, Patricia; Rodríguez, Natalia; Blázquez, Ana; Monteagudo, Ana; Boloc, Daniel; Plana, Maria Teresa; Lafuente, Amalia; Lázaro, Luisa; Arnaiz, Joan Albert; Mas, Sergi

2017-04-03

The serotonin 1B receptor (5-HT 1B ) is important to both the pathogenesis of major depressive disorder and the antidepressant effects of selective serotonin reuptake inhibitors. Although fluoxetine has been shown to be effective and safe in children and adolescents, not all patients experience a proper clinical response, which has led to further study into the main factors involved in this inter-individual variability. Our aim was to study the effect of epigenetic and genetic factors that could affect 5-hydroxytryptamine receptor 1B (HTR1B) gene expression, and thereby response to fluoxetine. A total of 83 children and adolescents were clinically assessed 12weeks after of initiating an antidepressant treatment with fluoxetine for the first time. We evaluated the influence of single nucleotide polymorphisms (SNPs) specifically located in transcription factor binding sites (TFBSs) on their clinical improvement. A combined genetic analysis considering the significant SNPs together with the functional variant rs130058 previously associated in our population was also performed. Moreover, we assessed, for the first time in the literature, whether methylation levels of the HTR1B promoter region could be associated with the pharmacological response. Two, rs9361233 and rs9361235, were significantly associated with clinical improvement after treatment with fluoxetine. The heterozygous genotype combination analysis showed a negative correlation with clinical improvement. The lowest improvement was experienced by patients who were heterozygous for all three SNPs. Moreover, a negative correlation was found between clinical improvement and the average methylation level of the HTR1B promoter. These results give new evidence for the role of epigenetic and genetic factors which could modulate HTR1B expression in the pharmacological response to antidepressants. Copyright © 2016 Elsevier Inc. All rights reserved.
Acute Treatment of Migraine

PubMed Central

ÖZTÜRK, Vesile

2013-01-01

Migraine is one of the most frequent disabling neurological conditions with a major impact on the patient’s quality of life. Migraine has been described as a chronic disorder that characterized with attacks. Attacks are characterized by moderate–severe, often unilateral, pulsating headache attacks, typically lasting 4 to 72 hours. Migraine remains underdiagnosed and undertreated despite advances in the understanding of its pathophysiology. This article reviews management of migraine acute pharmacological treatment. Currently, for the acute treatment of migraine attacks, non-steroidal anti-inflammatory drugs (NSAIDs) and triptans (serotonin 5HT1B/1D receptor agonists) are recommended. Before intake of NSAID and triptans, metoclopramide or domperidone is useful. In very severe attacks, subcutaneous sumatriptan is first choice. The patient should be treated early in the attack, use an adequate dose and formulation of a medication. Ideally, acute therapy should be restricted to no more than 2 to 3 days per week to avoid medication overuse. PMID:28360580
Molecular Docking and Pharmacological Investigations of Rivastigmine-Fluoxetine and Coumarin-Tacrine hybrids against Acetyl Choline Esterase.

PubMed

Babitha, Pallikkara Pulikkal; Sahila, Mohammed Marunnan; Bandaru, Srinivas; Nayarisseri, Anuraj; Sureshkumar, Sivanpillai

2015-01-01

The present AChE inhibitors have been successful in the treatment of Alzheimer׳s Diseases however suffers serious side effects. Therefore in this view, the present study was sought to identify compounds with appreciable pharmacological profile targeting AChE. Analogue of Rivastigmine and Fluoxetine hybrid synthesized by Toda et al, 2003 (dataset1), and Coumarin-Tacrine hybrids synthesized by Qi Sun et al (dataset2) formed the test compounds for the present pharmacological evaluation. p-cholorophenyl substituted Rivastigmine and Fluoxetine hybrid compound (26d) from dataset 1 and -OCH3 substitute Coumarin-Tacrine hybrids (1h) from dataset 2 demonstrated superior pharmacological profile. 26 d showed superior pharmacological profile comparison to the entire compounds in either dataset owing to its better electrostatic interactions and hydrogen bonding patterns. In order to identify still better compound with pharmacological profile than 26 d and 1h, virtual screening was performed. The best docked compound (PubCId: PubCid: 68874404) showed better affinity than its parent 26 d, however showed poor ADME profile and AMES toxicity. CHEMBL2391475 (PubCid: 71699632) similar to 1h had reduced affinity in comparison to its parent compound 1h. From, our extensive analysis involving binding affinity analysis, ADMET properties predictions and pharmacophoric mappings, we report p-cholorophenyl substituted rivastigmine and fluoxetine hybrid (26d) to be a potential candidate for AcHE inhibition which in addition can overcome narrow therapeutic window of present AChE inhibitors in clinical treatment of Alzheimer׳s disease. AD - Alzheimer׳s Disease, AChE - Acetyl Choline Estarase, OPLS - Optimized Potentials for Liquid Simulations, PDB - Protein Data Bank.
L-Acetylcarnitine in dysthymic disorder in elderly patients: a double-blind, multicenter, controlled randomized study vs. fluoxetine.

PubMed

Bersani, Giuseppe; Meco, Giuseppe; Denaro, Alessandro; Liberati, Damien; Colletti, Chiara; Nicolai, Raffaella; Bersani, Francesco Saverio; Koverech, Aleardo

2013-10-01

L-Acetylcarnitine (LAC), the acetyl ester of carnitine naturally present in the central nervous system and involved in several neural pathways, has been demonstrated to be active in various animal experimental models resembling some features of human depression. The aim of the study is to verify whether LAC can have an antidepressant action in a population of elderly patients with dysthymic disorder in comparison with a traditional antidepressant such as fluoxetine. Multicentric, double-blind, double-dummy, controlled, randomized study based on a observation period of 7 weeks. 80 patients with DSM-IV diagnosis of dysthymic disorder were enrolled in the study and subdivided into 2 groups. Group A patients received LAC plus placebo; group B patients received fluoxetine 20 mg/die plus placebo. Clinical assessment was performed through several psychometric scales at 6 different moments. Group A patients showed a statistically significant improvement in the following scales: HAM-D, HAM-A, BDI and Touluse Pieron Test. Comparison between the two groups, A and B, generally showed very similar clinical progression. The results obtained with LAC and fluoxetine were equivalent. As the subjects in this study were of senile age, it is possible to hypothesize that the LAC positive effect on mood could be associated with improvement in subjective cognitive symptomatology. The difference in the latency time of clinical response (1 week of LAC treatment, compared with the 2 weeks' latency time with fluoxetine) suggests the existence of different mechanisms of action possibly in relation to the activation of rapid support processes of neuronal activity. Copyright © 2012 Elsevier B.V. and ECNP. All rights reserved.
Sexual Pain among Malaysian Women Receiving Antidepressant: A Comparison between Escitalopram and Fluoxetine.

PubMed

Sidi, Hatta; Asmidar, Duni; Seng, Loh Huai; Jaafar, Nik Ruzyanei Nik; Midi, Marhani; Guan, Ng Chong

2016-03-01

The current study compares the risk of sexual pain in depressed female patients in remission between those who were treated with Escitalopram and Fluoxetine. The associated factors were also examined. This is a cross-sectional study involved 112 depressed female patients (56 treated with Escitalopram and 56 treated with Fluoxetine) who were in remission (as defined by Diagnostic and Statistical Manual-IV (DSM-IV) in the past 2 months and Montgomery-Asberg Depression Rating Scale (MADRS) score of ≤ 10) from the psychiatric clinic, University Kebangsaan Malaysia Medical Centre (UKMMC). They were interviewed using Structured Clinical Interview for DSM-IV (SCID). Hypoactive sexual desire was assessed using the Pain subscale of Malay Version of the Female Sexual Function Index (MVFSFI). The results show that risk of sexual pain was relatively low (16.07% for all patients), with no statistical significant between the two groups (17.86% for fluoxetine group, 14.29% for escitalopram group). Older age (adjusted odds ratio = 1.524, 95% CI = 1.199, 1.938) was the only factor significantly associated with sexual pain disorder. There should not be any barrier when continuing the use of escitalopram or fluoxetine as antidepressants amongst the female patients.
Proteomic characterization of hippocampus of chronically socially isolated rats treated with fluoxetine: Depression-like behaviour and fluoxetine mechanism of action.

PubMed

Perić, Ivana; Costina, Victor; Stanisavljević, Andrijana; Findeisen, Peter; Filipović, Dragana

2018-06-01

Due to the severity of depressive symptoms, there remains a necessity in defining the underlying mechanisms of depression and the precise actions of antidepressants in alleviating these symptoms. Proteomics is a powerful and promising tool for discovering novel pathways of cellular responses to disease and treatment. As chronic social isolation (CSIS) is a valuable animal model for studying depression, we performed a comparative subproteomic study of rat hippocampus to explore the effect of six weeks of CSIS and the therapeutic effect of chronic fluoxetine (Flx) treatment (last three weeks of CSIS; 15 mg/kg/day). Behaviorally, Flx treatment normalized the decreased sucrose preference and increased marble burying results resulting from CSIS, indicative of a FLX-induced attenuation of both anhedonia and anxiety. An analysis of cytosolic and nonsynaptic mitochondrial subproteome patterns revealed that CSIS resulted in down-regulation of proteins involved in mitochondrial transport and energy processes, primarily tricarboxylic acid (TCA) cycle and oxidative phosphorylation. Chronic Flx treatment resulted in an up-regulation of CSIS-altered proteins and additional expression of other transporter and energy-involved proteins. Immunohistochemical analysis revealed hippocampal subregion-specific effects of CSIS and/or Flx treatment on selective protein expressions. Copyright © 2018 Elsevier Ltd. All rights reserved.
Quantitative Cross-Species Extrapolation between Humans and Fish: The Case of the Anti-Depressant Fluoxetine

PubMed Central

Margiotta-Casaluci, Luigi; Owen, Stewart F.; Cumming, Rob I.; de Polo, Anna; Winter, Matthew J.; Panter, Grace H.; Rand-Weaver, Mariann; Sumpter, John P.

2014-01-01

Fish are an important model for the pharmacological and toxicological characterization of human pharmaceuticals in drug discovery, drug safety assessment and environmental toxicology. However, do fish respond to pharmaceuticals as humans do? To address this question, we provide a novel quantitative cross-species extrapolation approach (qCSE) based on the hypothesis that similar plasma concentrations of pharmaceuticals cause comparable target-mediated effects in both humans and fish at similar level of biological organization (Read-Across Hypothesis). To validate this hypothesis, the behavioural effects of the anti-depressant drug fluoxetine on the fish model fathead minnow (Pimephales promelas) were used as test case. Fish were exposed for 28 days to a range of measured water concentrations of fluoxetine (0.1, 1.0, 8.0, 16, 32, 64 µg/L) to produce plasma concentrations below, equal and above the range of Human Therapeutic Plasma Concentrations (HTPCs). Fluoxetine and its metabolite, norfluoxetine, were quantified in the plasma of individual fish and linked to behavioural anxiety-related endpoints. The minimum drug plasma concentrations that elicited anxiolytic responses in fish were above the upper value of the HTPC range, whereas no effects were observed at plasma concentrations below the HTPCs. In vivo metabolism of fluoxetine in humans and fish was similar, and displayed bi-phasic concentration-dependent kinetics driven by the auto-inhibitory dynamics and saturation of the enzymes that convert fluoxetine into norfluoxetine. The sensitivity of fish to fluoxetine was not so dissimilar from that of patients affected by general anxiety disorders. These results represent the first direct evidence of measured internal dose response effect of a pharmaceutical in fish, hence validating the Read-Across hypothesis applied to fluoxetine. Overall, this study demonstrates that the qCSE approach, anchored to internal drug concentrations, is a powerful tool to guide the
Rapid Response to Treatment for Binge Eating Disorder

ERIC Educational Resources Information Center

Grilo, Carlos M.; Masheb, Robin M.; Wilson, Terence G.

2006-01-01

The authors examined rapid response among 108 patients with binge eating disorder (BED) who were randomly assigned to 1 of 4 16-week treatments: fluoxetine, placebo, cognitive-behavioral therapy (CBT) plus fluoxetine, or CBT plus placebo. Rapid response, defined as 65% or greater reduction in binge eating by the 4th treatment week, was determined…
Pharmacotherapy with Fluoxetine Restores Functional Connectivity from the Dentate Gyrus to Field CA3 in the Ts65Dn Mouse Model of Down Syndrome

PubMed Central

Guidi, Sandra; Ciani, Elisabetta; Mangano, Chiara; Calzà, Laura; Bartesaghi, Renata

2013-01-01

Down syndrome (DS) is a high-incidence genetic pathology characterized by severe impairment of cognitive functions, including declarative memory. Impairment of hippocampus-dependent long-term memory in DS appears to be related to anatomo-functional alterations of the hippocampal trisynaptic circuit formed by the dentate gyrus (DG) granule cells - CA3 pyramidal neurons - CA1 pyramidal neurons. No therapies exist to improve cognitive disability in individuals with DS. In previous studies we demonstrated that pharmacotherapy with fluoxetine restores neurogenesis, granule cell number and dendritic morphology in the DG of the Ts65Dn mouse model of DS. The goal of the current study was to establish whether treatment rescues the impairment of synaptic connectivity between the DG and CA3 that characterizes the trisomic condition. Euploid and Ts65Dn mice were treated with fluoxetine during the first two postnatal weeks and examined 45–60 days after treatment cessation. Untreated Ts65Dn mice had a hypotrophyc mossy fiber bundle, fewer synaptic contacts, fewer glutamatergic contacts, and fewer dendritic spines in the stratum lucidum of CA3, the terminal field of the granule cell projections. Electrophysiological recordings from CA3 pyramidal neurons showed that in Ts65Dn mice the frequency of both mEPSCs and mIPSCs was reduced, indicating an overall impairment of excitatory and inhibitory inputs to CA3 pyramidal neurons. In treated Ts65Dn mice all these aberrant features were fully normalized, indicating that fluoxetine can rescue functional connectivity between the DG and CA3. The positive effects of fluoxetine on the DG-CA3 system suggest that early treatment with this drug could be a suitable therapy, possibly usable in humans, to restore the physiology of the hippocampal networks and, hence, memory functions. PMID:23620781
Adolescent fluoxetine exposure produces enduring, sex-specific alterations of visual discrimination and attention in rats.

PubMed

LaRoche, Ronee B; Morgan, Russell E

2007-01-01

Over the past two decades the use of selective serotonin reuptake inhibitors (SSRIs) to treat behavioral disorders in children has grown rapidly, despite little evidence regarding the safety and efficacy of these drugs for use in children. Utilizing a rat model, this study investigated whether post-weaning exposure to a prototype SSRI, fluoxetine (FLX), influenced performance on visual tasks designed to measure discrimination learning, sustained attention, inhibitory control, and reaction time. Additionally, sex differences in response to varying doses of fluoxetine were examined. In Experiment 1, female rats were administered (P.O.) fluoxetine (10 mg/kg ) or vehicle (apple juice) from PND 25 thru PND 49. After a 14 day washout period, subjects were trained to perform a simultaneous visual discrimination task. Subjects were then tested for 20 sessions on a visual attention task that consisted of varied stimulus delays (0, 3, 6, or 9 s) and cue durations (200, 400, or 700 ms). In Experiment 2, both male and female Long-Evans rats (24 F, 24 M) were administered fluoxetine (0, 5, 10, or 15 mg/kg) then tested in the same visual tasks used in Experiment 1, with the addition of open-field and elevated plus-maze testing. Few FLX-related differences were seen in the visual discrimination, open field, or plus-maze tasks. However, results from the visual attention task indicated a dose-dependent reduction in the performance of fluoxetine-treated males, whereas fluoxetine-treated females tended to improve over baseline. These findings indicate that enduring, behaviorally-relevant alterations of the CNS can occur following pharmacological manipulation of the serotonin system during postnatal development.
Effects of Sequential Fluoxetine and Gender on Pre-quit Depressive Symptoms, Affect, Craving, and Quit Day Abstinence in Smokers with Elevated Depressive Symptoms: A Growth Curve Modeling Approach

PubMed Central

Minami, Haruka; Kahler, Christopher W.; Bloom, Erika Litvin; Prince, Mark A.; Abrantes, Ana M.; Strong, David R.; Niaura, Raymond; Miller, Ivan W.; Palm Reed, Kathleen M.; Price, Lawrence H.; Brown, Richard A.

2015-01-01

While the important roles of post-quit affect and withdrawal symptoms in the process of smoking cessation have been well established, little is known about the relations between pre-quit affective trajectories and cessation outcome on the target quit date (TQD). This study examined whether a 16-week course of fluoxetine initiated 8 weeks pre-quit (“sequential” fluoxetine) improved TQD abstinence relative to placebo through its effects on pre-quit depressive symptoms, affect (withdrawal-relevant negative affect, general negative affect, and positive affect), and craving to smoke among 206 smokers with elevated depressed symptoms. The moderating effects of gender were also examined. A total of 83 smokers (40%) failed to achieve abstinence on TQD, with no difference between treatment conditions or gender. Overall structural equation models showed that fluoxetine had significant indirect effects on TQD abstinence through changes in pre-quit withdrawal-relevant negative affect and craving, but not depressive symptoms. However, multigroup analyses revealed gender differences. Sequential fluoxetine reduced pre-quit depressive symptoms, withdrawal-relevant negative affect, and craving only among women. Reduction in pre-quit depressive symptoms and craving among women, and withdrawal-relevant negative affect among men was associated with TQD abstinence. Moreover, exploratory analysis showed negative trend-level indirect effects of fluoxetine on TQD abstinence via increased side effects, regardless of gender. This study demonstrated the importance of considering gender when examining treatment efficacy. Identifying ways to further reduce pre-quit depressive symptoms and craving for women and withdrawal-relevant negative affect for men while alleviating side effects may help smokers with elevated depressed symptoms achieve the first smoking cessation milestone. PMID:25089930

Sexual Pain among Malaysian Women Receiving Antidepressant: A Comparison between Escitalopram and Fluoxetine

PubMed Central

Sidi, Hatta; Asmidar, Duni; Seng, Loh Huai; Jaafar, Nik Ruzyanei Nik; Midi, Marhani; Guan, Ng Chong

2016-01-01

Objectives The current study compares the risk of sexual pain in depressed female patients in remission between those who were treated with Escitalopram and Fluoxetine. The associated factors were also examined. Methods This is a cross-sectional study involved 112 depressed female patients (56 treated with Escitalopram and 56 treated with Fluoxetine) who were in remission (as defined by Diagnostic and Statistical Manual-IV (DSM-IV) in the past 2 months and Montgomery-Asberg Depression Rating Scale (MADRS) score of ≤ 10) from the psychiatric clinic, University Kebangsaan Malaysia Medical Centre (UKMMC). They were interviewed using Structured Clinical Interview for DSM-IV (SCID). Hypoactive sexual desire was assessed using the Pain subscale of Malay Version of the Female Sexual Function Index (MVFSFI). Results The results show that risk of sexual pain was relatively low (16.07% for all patients), with no statistical significant between the two groups (17.86% for fluoxetine group, 14.29% for escitalopram group). Older age (adjusted odds ratio = 1.524, 95% CI = 1.199, 1.938) was the only factor significantly associated with sexual pain disorder. Conclusions There should not be any barrier when continuing the use of escitalopram or fluoxetine as antidepressants amongst the female patients. PMID:27738371
Effect of comorbid tics on a clinically meaningful response to 8-week open-label trial of fluoxetine in obsessive compulsive disorder.

PubMed

Husted, David S; Shapira, Nathan A; Murphy, Tanya K; Mann, Giselle D; Ward, Herbert E; Goodman, Wayne K

2007-01-01

Currently, there are limited published data evaluating the effects of tics on serotonin reuptake inhibitor (SRI) monotherapy responses in treating obsessive-compulsive disorder (OCD). One retrospective case-controlled analysis of OCD patients treated with SRI monotherapy showed lesser improvement in OCD symptoms in patients with tics than those without. However, more recently there were preliminary reports of OCD subjects treated with SRI monotherapy which did not demonstrate poorer response in subjects with tics or Tourette's Syndrome (TS). The specific aim of this study was to investigate whether the presence of comorbid chronic tics affected "clinically meaningful improvement" [McDougle, C.J., Goodman, W.K., Leckman, J.F., Barr, L.C., Heninger, G.R., Price, L.H., 1993. The efficacy of fluvoxamine in obsessive-compulsive disorder: effects of comorbid chronic tic disorder. Journal of Clinical Psychopharmacology 13, 354-358] of OCD in an 8-week open-label trial of fluoxetine monotherapy. Seventy-four adult subjects (13 patients with comorbid chronic tics and 61 patients without tics) with a primary DSM-IV OCD diagnosis were treated with up to 40mg fluoxetine for 8 weeks and had at least one post-baseline evaluation. The results indicate that there was a significant response by time in both fluoxetine-with-tic subjects and fluoxetine-without-tic subjects. Additionally, there were 3 (23.0%) OCD subjects with tics who had clinically meaningful improvement versus 16 (26.2%) OCD subjects without tics that demonstrated similar levels of improvement. These findings indicate that OCD patients with or without chronic tic disorders did not have a differential response to an 8-week open-label trial of fluoxetine. Limitations include the relatively low number of tic subjects and the open-label nature of the study. Additional data are needed on how comorbid tics may affect SRI treatment response in OCD.
The effect of chronic fluoxetine on social isolation-induced changes on sucrose consumption, immobility behavior, and on serotonin and dopamine function in hippocampus and ventral striatum.

PubMed

Brenes, Juan C; Fornaguera, Jaime

2009-03-02

This study examined the effect of fluoxetine, a selective serotonin (5-HT) reuptake inhibitor, on isolation-induced changes on sucrose consumption and preference, spontaneous open-field activity, forced swimming behavior, and on tissue levels of 5-HT and dopamine (DA) in hippocampus and ventral striatum (VS). Male Sprague-Dawley rats were reared in social isolation or group housing from postnatal day 28. Thirty-two days later, half of the isolated animals were orally treated with fluoxetine (10mg/kg/day) during the following 34 days. At the end of this period, behavior was assessed and afterward ex-vivo tissue samples were obtained. It was found that fluoxetine restored isolation-increased sucrose consumption and immobility behavior, without affecting locomotor activity, which appeared slightly increased in isolated groups both treated and untreated. In the hippocampus, isolation rearing depleted 5-HT contents and increased 3,4-dihydroxyphenylacetic acid (DOPAC) levels, as well as 5-HT and DA turnover. These neurochemical alterations were reversed by fluoxetine. In VS, treated and untreated isolated rats showed higher 5-HT levels than grouped congeners. Although fluoxetine did not affect 5-HT and DA contents in this region, it slightly reversed the alterations in the 5-HT and DA turnover observed in isolated rats. Overall, social isolation impaired incentive and escape motivated behaviors. At the neurochemical level, isolation rearing affected 5-HT rather than DA activity, and this differential effect was more noticeable in hippocampus than in VS. The chronic treatment with fluoxetine during the last month of rearing somewhat prevented these behavioral and neurochemical alterations. Our data suggest that isolation rearing is an appropriate procedure to model some developmental-related alterations underlying depression disorders.
The antidepressant fluoxetine alters mechanisms of pre- and post-copulatory sexual selection in the eastern mosquitofish (Gambusia holbrooki).

PubMed

Bertram, Michael G; Ecker, Tiarne E; Wong, Bob B M; O'Bryan, Moira K; Baumgartner, John B; Martin, Jake M; Saaristo, Minna

2018-03-19

Contamination of aquatic habitats with pharmaceuticals is a major environmental concern. Recent studies have detected pharmaceutical pollutants in a wide array of ecosystems and organisms, with many of these contaminants being highly resistant to biodegradation and capable of eliciting sub-lethal effects in non-target species. One such pollutant is fluoxetine, a widely prescribed antidepressant, which is frequently detected in surface waters globally and can alter physiology and behaviour in aquatic organisms. Despite this, relatively little is known about the potential for fluoxetine to disrupt mechanisms of sexual selection. Here, we investigate the impacts of 30-day exposure to two environmentally realistic levels of fluoxetine (low and high) on mechanisms of pre- and post-copulatory sexual selection in the eastern mosquitofish (Gambusia holbrooki). We tested 1) male mating behaviour in the absence or presence of a competitor male, and 2) sperm quality and quantity. We found that high-fluoxetine exposure increased male copulatory behaviour in the absence of a competitor, while no effect was detected under male-male competition. Further, fluoxetine exposure at both concentrations increased total sperm count relative to males from the control group, while no significant change in sperm quality was observed. Lastly, low-fluoxetine males showed a significant reduction in condition index (mass relative to length). Our study is the first to show altered mechanisms of both pre- and post-copulatory sexual selection in an aquatic species resulting from environmentally realistic fluoxetine exposure, highlighting the capacity of pharmaceutical pollution to interfere with sensitive reproductive processes in wildlife. Copyright © 2018 Elsevier Ltd. All rights reserved.
Brain region- and sex-specific modulation of mitochondrial glucocorticoid receptor phosphorylation in fluoxetine treated stressed rats: effects on energy metabolism.

PubMed

Adzic, Miroslav; Lukic, Iva; Mitic, Milos; Djordjevic, Jelena; Elaković, Ivana; Djordjevic, Ana; Krstic-Demonacos, Marija; Matić, Gordana; Radojcic, Marija

2013-12-01

Antidepressants affect glucocorticoid receptor (GR) functioning partly through modulation of its phosphorylation but their effects on mitochondrial GR have remained undefined. We investigated the ability of chronic fluoxetine treatment to affect chronic stress-induced changes of mitochondrial GR and its phosphoisoforms (pGRs) in the prefrontal cortex and hippocampus of female and male rats. Since mitochondrial GR regulates oxidative phosphorylation, expression of mitochondrial-encoded subunits of cytochrome (cyt) c oxidase and its activity were also investigated. Chronic stress caused accumulation of the GR in mitochondria of female prefrontal cortex, while the changes in the hippocampus were sex-specific at the levels of pGRs. Expression of mitochondrial COXs genes corresponded to chronic stress-modulated mitochondrial GR in both tissues of both genders and to cyt c oxidase activity in females. Moreover, the metabolic parameters in stressed animals were affected by fluoxetine therapy only in the hippocampus. Namely, fluoxetine effects on mitochondrial COXs and cyt c oxidase activity in the hippocampus seem to be conveyed through pGR232 in females, while in males this likely occurs through other mechanisms. In summary, sex-specific regulation of cyt c oxidase by the stress and antidepressant treatment and its differential convergence with mitochondrial GR signaling in the prefrontal cortex and hippocampus could contribute to clarification of sex-dependent vulnerability to stress-related disorders and sex-specific clinical impact of antidepressants. Copyright © 2013 Elsevier Ltd. All rights reserved.
Effects of acute administration of selective serotonin reuptake inhibitors on sympathetic nerve activity

PubMed Central

Tiradentes, R.V.; Pires, J.G.P.; Silva, N.F.; Ramage, A.G.; Santuzzi, C.H.; Futuro, H.A.

2014-01-01

Serotonergic mechanisms have an important function in the central control of circulation. Here, the acute effects of three selective serotonin (5-HT) reuptake inhibitors (SSRIs) on autonomic and cardiorespiratory variables were measured in rats. Although SSRIs require 2-3 weeks to achieve their full antidepressant effects, it has been shown that they cause an immediate inhibition of 5-HT reuptake. Seventy male Wistar rats were anesthetized with urethane and instrumented to record blood pressure, heart rate, renal sympathetic nerve activity (RSNA), and respiratory frequency. At lower doses, the acute cardiovascular effects of fluoxetine, paroxetine and sertraline administered intravenously were insignificant and variable. At middle and higher doses, a general pattern was observed, with significant reductions in sympathetic nerve activity. At 10 min, fluoxetine (3 and 10 mg/kg) reduced RSNA by -33±4.7 and -31±5.4%, respectively, without changes in blood pressure; 3 and 10 mg/kg paroxetine reduced RSNA by -35±5.4 and -31±5.5%, respectively, with an increase in blood pressure +26.3±2.5; 3 mg/kg sertraline reduced RSNA by -59.4±8.6%, without changes in blood pressure. Sympathoinhibition began 5 min after injection and lasted approximately 30 min. For fluoxetine and sertraline, but not paroxetine, there was a reduction in heart rate that was nearly parallel to the sympathoinhibition. The effect of these drugs on the other variables was insignificant. In conclusion, acute peripheral administration of SSRIs caused early autonomic cardiovascular effects, particularly sympathoinhibition, as measured by RSNA. Although a peripheral action cannot be ruled out, such effects are presumably mostly central. PMID:25003632
Metabolomic identification of biochemical changes induced by fluoxetine and imipramine in a chronic mild stress mouse model of depression

NASA Astrophysics Data System (ADS)

Zhao, Jing; Jung, Yang-Hee; Jang, Choon-Gon; Chun, Kwang-Hoon; Kwon, Sung Won; Lee, Jeongmi

2015-03-01

Metabolomics was applied to a C57BL/6N mouse model of chronic unpredictable mild stress (CMS). Such mice were treated with two antidepressants from different categories: fluoxetine and imipramine. Metabolic profiling of the hippocampus was performed using gas chromatography-mass spectrometry analysis on samples prepared under optimized conditions, followed by principal component analysis, partial least squares-discriminant analysis, and pair-wise orthogonal projections to latent structures discriminant analyses. Body weight measurement and behavior tests including an open field test and the forced swimming test were completed with the mice as a measure of the phenotypes of depression and antidepressive effects. As a result, 23 metabolites that had been differentially expressed among the control, CMS, and antidepressant-treated groups demonstrated that amino acid metabolism, energy metabolism, adenosine receptors, and neurotransmitters are commonly perturbed by drug treatment. Potential predictive markers for treatment effect were identified: myo-inositol for fluoxetine and lysine and oleic acid for imipramine. Collectively, the current study provides insights into the molecular mechanisms of the antidepressant effects of two widely used medications.
Adolescent fluoxetine treatment decreases the effects of neonatal immune activation on anxiety-like behavior in mice.

PubMed

Majidi-Zolbanin, Jafar; Azarfarin, Maryam; Samadi, Hanieh; Enayati, Mohsen; Salari, Ali-Akbar

2013-08-01

Experimental studies have shown conflicting effects of neonatal infection on anxiety-like behaviors and hypothalamic-pituitary-adrenal (HPA) axis activity in adult rats. We investigated for the first time whether neonatal exposure to lipopolysaccharide (LPS) is associated with increased levels of anxiety-like behaviors in mice. Moreover, there have been several studies showing that adolescent fluoxetine (FLX) treatment can influence HPA axis development and prevent occurrence of psychiatric disorders induced by common early-life insults. In the present study, we also investigated the effects of adolescent FLX exposure following neonatal immune activation on anxiety-like behavior in mice. Neonatal mice were treated to LPS (50μg/kg) or saline on postnatal days (PND) 3 and 5, then male and female mice of both neonatal intervention groups received oral administration of FLX (5 and 10mg/kg/day) or water via regular drinking bottles during the adolescent period (PNDs 35-65). The results showed that postnatal immune challenge increased anxiety-like behavior in the open field, elevated plus-maze and light-dark box in adult mice (PND 90). Furthermore, the adolescent FLX treatment inhibited the anxiety-like behavior induced by neonatal infection in both sexes. However, this study indicates the negative effects of the FLX on normal behavioral symptoms in male control mice. Taken together, the current data provide experimental evidence that neonatal infection increases anxiety levels in male and female mice in adulthood. Additionally, the findings of this study support the hypothesis that an early pharmacological intervention with FLX may be an effective treatment for reducing the behavioral abnormalities induced by common early-life insults. Copyright © 2013 Elsevier B.V. All rights reserved.
Emerging Hyperprolactinemic Galactorrhea in Obsessive Compulsive Disorder with a Stable Dose of Fluoxetine.

PubMed

Chatterjee, Seshadri Sekhar; Mitra, Sayantanava; Mallik, Nitu

2015-12-31

While fluoxetine (FXT) is a frequently prescribed selective serotonin reuptake inhibitor (SSRI), with few major side-effects; altered serotonergic transmissions in hypothalamic pathways might lead to a distressing, and often embarrassing, manifestation of galactorrhea by altering prolactin release in those on FXT. We report here a case of FXT-induced hyperprolactinemic galactorrhea developing late into treatment on a stable regimen, who responded well to subsequent replacement with sertraline. Based on present finding, we suggest that while SSRIs may share similar mechanisms of action, there exist individual differences in their effects on prolactin secretion pathways.
Reduced vasopressin receptors activation mediates the anti-depressant effects of fluoxetine and venlafaxine in bulbectomy model of depression.

PubMed

Poretti, María Belén; Sawant, Rahul S; Rask-Andersen, Mathias; de Cuneo, Marta Fiol; Schiöth, Helgi B; Perez, Mariela F; Carlini, Valeria Paola

2016-03-01

In response to stress, corticotropin releasing hormone (CRH) and vasopressin (AVP) are released from the hypothalamus, activate their receptors (CRHR1, CRHR2 or AVPr1b), and synergistically act to induce adrenocorticotropic hormone (ACTH) release from the anterior pituitary. Overstimulation of this system has been frequently associated with major depression states. The objective of the study is to assess the role of AVP and CRH receptors in fluoxetine and venlafaxine effects on the expression of depression-related behavior. In an animal model of depression (olfactory bulbectomy in mice, OB), we evaluated the effects of fluoxetine or venlafaxine (both 10 mg/kg/day) chronic administration on depression-related behavior in the tail suspension test. Plasma levels of AVP, CRH, and ACTH were determined as well as participation of their receptors in the expression of depression related-behavior and gene expression of AVP and CRH receptors (AVPr1b, CRHR1, and CRHR2) in the pituitary gland. The expression of depressive-like behavior in OB animals was reversed by treatment with both antidepressants. Surprisingly, OB-saline mice exhibited increased AVP and ACTH plasma levels, with no alterations in CRH levels when compared to sham mice. Chronic fluoxetine or venlafaxine reversed these effects. In addition, a significant increase only in AVPr1b gene expression was found in OB-saline. The antidepressant therapy used seems to be more likely related to a reduced activation of AVP rather than CRH receptors, since a positive correlation between AVP levels and depressive-like behavior was observed in OB animals. Furthermore, a full restoration of depressive behavior was observed in OB-fluoxetine- or venlafaxine-treated mice only when AVP was centrally administered but not CRH.
Evaluation of the stability of fluoxetine in pluronic lecithin organogel and the determination of an appropriate beyond-use date.

PubMed

Peacock, Gina F; Sauvageot, Jurgita

2014-01-01

Fluoxetine is a commonly prescribed psychotropic medication for a variety of behavioral diagnoses in veterinary practice, and fluoxetine in Pluronic lecithin organogel has been used successfully in treating inappropriate urine spraying in felines. Historically, pharmacists have assigned a variety of beyond-use dates to extemporaneously compound drugs in Pluronic lecithin organogel. The objective of this study was to evaluate the stability of fluoxetine in Pluronic lecithin organogel over a period of six months and to determine an appropriate beyond-use date. A stability-indicating high-performance liquid chromatography method for fluoxetine in Pluronic lecithin organogel was validated in our laboratory. Fluoxetine-Pluronic lecithin organogel 50 mg/mL was prepared by a local compounding pharmacy and analyzed by high-performance liquid chromatograph at 0, 7, 14, 21, 28, 45, 60, 90, and 180 days. Physical stability was also assessed by visual observation. At each time point percent of initial concentration was calculated. The beyond-use date was determined as the time period that the samples maintained at least 90 percent of the initial concentration. At 180 days, the mean percent of initial concentration was 99 +/- 1.5 and, visually, the fluoxetine-Pluronic lecithin organogel retained the original color and consistency, without detectable separation of the different phases of Pluronic lecithin organogel. Since fluoxetine was physically stable and retained greater than 90 percent of initial concentration in Pluronic lecithin organogel for 180 days when stored at room temperature and protected from light, a beyond-use date of 180 days is appropriate.
Antidepressant-like effect of fluoxetine may depend on translocator protein activity and pretest session duration in forced swimming test in mice.

PubMed

Kudryashov, Nikita V; Kalinina, Tatiana S; Shimshirt, Alexander A; Korolev, Anton O; Volkova, Anna V; Voronina, Tatiana A

2018-06-01

The antidepressant-like effect of fluoxetine (20 mg/kg i.p.) has been assessed using the forced swimming test (FST) in IRC (CD-1) mice exposed or not to a pretest session of different duration (5 or 20 min). The influence of the mitochondrial translocator protein (TSPO) activity on the antidepressant-like effect of fluoxetine (20 mg/kg i.p.) in the FST was also studied. The antidepressant-like effect of fluoxetine was observed only in mice subjected to a 5-min pretest session 24 h before the FST. The TSPO antagonist PK11195 [1-(2-chlorophenyl)-N-methyl-N-(1-methylpropyl)-3-isoquinolinecarboxamide; 1 or 3 mg/kg i.p.] inhibited the antidepressant activity of fluoxetine in the FST. In the present study, fluoxetine or PK11195 was administered for a short duration. We suppose that the functional activity of TSPO may depend on a pretest session and that using this procedure is necessary to detect antidepressant activity of fluoxetine-like drugs.
Sexual arousal difficulties in women treated with antidepressants: a comparison between escitalopram and fluoxetine.

PubMed

Midi, Marhani; Kanagasundram, Sharmilla; Sidi, Hatta; Asmidar, Duni; Naing, Ling; Guan, Ng Chong

2012-01-01

To compare the risk of sexual arousal difficulties between two groups of depressed female patients in remission who were treated with either escitalopram or fluoxetine. Associated factors were also examined. This was a cross-sectional study involving 112 female patients attending the psychiatric clinic, University Kebangsaan Malaysia Medical Centre (UKMMC) with depressive disorders as assessed by using the Structured Clinical Interview for DSM-IV (SCID), who had been in remission for the previous 2 months as defined by a score of < or = 10 from an assessment using the Montgomery-Asberg Depression Rating Scale (MADRS) and were treated with either fluoxetine or escitalopram. Sexual arousal difficulties were assessed using the arousal subscale of Malay Version of the Female Sexual Function Index (MVFSFI). The rate of sexual arousal difficulties was 41.1% for all subjects. Sexual arousal difficulties occurred in 50.0% of subjects treated with fluoxetine and 32.1% with escitalopram. However, this difference was not statistically significant (p = 0.055). Multivariate logistic regression analysis showed that higher dose of antidepressant (adjusted OR = 4.08, 95 CI = 1.70-9.81) was significantly associated with female sexual arousal difficulties. The risk of sexual arousal difficulties was higher in female patients who were treated with higher doses of either fluoxetine or escitalopram.
[Effects of Fluoxetine on Nogo Expression and Collagen Production with Decrease of Pulmonary Artery Pressure in Rats with Right Ventricular Failure.

PubMed

Ran, Xun; Zhao, Jian-Xun; Nie, Hu; Chen, Yu-Cheng

2016-11-01

To investigate the effect of fluoxetine on neurite growth inhibitor (Nogo) expession and collagen production of cardiac tissue in rats with right heart failure and pulmonary hypertension. Thirty one male SD rats were randomly divided into the treatment group,right heart failure group and normal control group.The rats in the treatment group and right heart failure group received intrapertioneal injection of monocrotaline (MCT,60 mg/kg) to induce pulmonary hypertension and right heart failure.After 21 days,the rats in treatment group were given fluoxetine of 10 mg/(kg×d) by gavage per day for 21 days,the rats in the other two groups were given saline.HE staining was used to observe the pulmonary artery and right ventricular myocardial tissue in rats.The collagen formation in right ventricular myocardium was observed by Masson staining.The expressions of Nogo-A, Nogo-B ,type1collagen and type 3 collagen mRNA in myocardium were measured by real-time fluorescence quantitative PCR,while the semi quantitative measurement of Nogo protein level was detected by Western blot. After the intervention of fluoxetine,pulmonary artery stenosis was significantly reduced,myocardial tissue lesion decreased,collagen synthesis decreased in right ventricular myocardium.RT-PCR showed that mRNA of Nogo-A decreased,and mRNA of Nogo-B increased ( P <0.05).Western blot showed that the expression of Nogo-A protein decreased,while Nogo-B1 protein expression increased ( P <0.05),Nogo-B2 expression was not significantly changed ( P >0.05). Nogo may affect the collagen synthesis in right heart failure,and partly involved in myocardial fibrosis.
Non-classical mechanism of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor channel block by fluoxetine.

PubMed

Barygin, Oleg I; Komarova, Margarita S; Tikhonova, Tatiana B; Tikhonov, Denis B

2015-04-01

Antidepressants have many targets in the central nervous system. A growing body of data demonstrates the influence of antidepressants on glutamatergic neurotransmission. In the present work, we studied the inhibition of native Ca(2+)-permeable and Ca(2+)-impermeable α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors in rat brain neurons by fluoxetine. The Ca(2+)-impermeable AMPA receptors in CA1 hippocampal pyramidal neurons were weakly affected. The IC50 value for the inhibition of Ca(2+)-permeable AMPA receptors in giant striatal interneurons was 43 ± 7 μM. The inhibition of Ca(2+)-permeable AMPA receptors was voltage dependent, suggesting deep binding in the pore. However, the use dependence of fluoxetine action differed markedly from that of classical AMPA receptor open-channel blockers. Moreover, fluoxetine did not compete with other channel blockers. In contrast to fluoxetine, its membrane-impermeant quaternary analog demonstrated all of the features of channel inhibition typical for open-channel blockers. It is suggested that fluoxetine reaches the binding site through a hydrophobic access pathway. Such a mechanism of block is described for ligands of sodium and calcium channels, but was never found in AMPA receptors. Molecular modeling suggests binding of fluoxetine in the subunit interface; analogous binding was proposed for local anesthetics in closed sodium channels and for benzothiazepines in calcium channels. © 2014 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.
An investigation of the representativity of neuropsychiatrists and their patients in a drug utilization observation study on fluoxetine.

PubMed

Schaaf, B; Linden, M; Weber, H J

1997-01-01

This study presents a methodological approach to an expost facto investigation of sample bias in drug utilization observation (DUO) studies using the example of a DUO with the nontricyclic antidepressant fluoxetine. A total of 479 psychiatrists and neurologists and 2,401 patients were investigated. The purpose of the study was to judge the representativeness of our DUO sample for two populations: first, for all psychiatrics and neurologists prescribing fluoxetine or all patients being treated with fluoxetine in Germany and, second, for all psychiatrists and neurologists prescribing antidepressants or all patients being treated with antidepressants in Germany. Criteria for the representativeness test were physician variables (gender, size of community where practicing, federal state, age, volume of prescriptions) and patient variables (gender, age, prescription-related diagnosis, concurrent illnesses, concomitant medications). The study shows that the DUO sample can rightfully claim representativeness in the majority of parameters for the psychiatrists and neurologists prescribing fluoxetine and for the patients being treated with fluoxetine. There are more noticeable discrepancies with regard to the psychiatrists and neurologists in general and to the patients being treated with antidepressants in general. The methodological problems of pharmacoepidemiological investigation of representativeness are discussed.
Association between Repeated Unpredictable Chronic Mild Stress (UCMS) Procedures with a High Fat Diet: A Model of Fluoxetine Resistance in Mice

PubMed Central

Isingrini, Elsa; Camus, Vincent; Le Guisquet, Anne-Marie; Pingaud, Maryse; Devers, Séverine; Belzung, Catherine

2010-01-01

Major depressive disorder is a debilitating disease. Unfortunately, treatment with antidepressants (ADs) has limited therapeutic efficacy since resistance to AD is common. Research in this field is hampered by the lack of a reliable natural animal model of AD resistance. Depression resistance is related to various factors, including the attendance of cardiovascular risk factors and past depressive episodes. We aimed to design a rodent model of depression resistance to ADs, associating cardiovascular risk factors with repeated unpredicted chronic mild stress (UCMS). Male BALB/c mice were given either a regular (4% fat) or a high fat diet (45% fat) and subjected to two 7-week periods of UCMS separated by 6 weeks. From the second week of each UCMS procedure, vehicle or fluoxetine (10 mg/kg, i.p.) was administrated daily. The effects of the UCMS and fluoxetine in both diet conditions were assessed using physical (coat state and body weight) and behavioural tests (the reward maze test and the splash test). The results demonstrate that during the second procedure, UCMS induced behavioural changes, including coat state degradation, disturbances in self-care behaviour (splash test) and anhedonia (reward maze test) and these were reversed by fluoxetine in the regular diet condition. In contrast, the high-fat diet regimen prevented the AD fluoxetine from abolishing the UCMS-induced changes. In conclusion, by associating UCMS—an already validated animal model of depression—with high-fat diet regimen, we designed a naturalistic animal model of AD resistance related to a sub-nosographic clinical entity of depression. PMID:20436931
A comparison of patterns of spontaneous adverse drug reaction reporting with St. John's Wort and fluoxetine during the period 2000-2013.

PubMed

Hoban, Claire L; Byard, Roger W; Musgrave, Ian F

2015-07-01

Herbal medicines are perceived to be safe by the general public and medical practitioners, despite abundant evidence from clinical trials and case reports that show herbal preparations can have significant adverse effects. The overall impact of adverse events to herbal medicines in Australia is currently unknown. Post marketing surveillance of medications through spontaneous adverse drug reaction (ADR) reports to the Therapeutic Goods Administration (TGA) is one way to estimate this risk. The patterns of spontaneously reported ADRs provide insight to herbal dangers, especially when compared with patterns of a mechanistically similar conventional drug. The study compared the pattern of spontaneously reported ADRs to St. John's Wort (Hypericum perforatum), a common herbal treatment for depression which contains selective serotonin reuptake inhibitors (SSRI), to fluoxetine, a commonly prescribed synthetic SSRI antidepressant. Spontaneous ADR reports sent to the TGA between 2000-2013 for St. John's Wort (n = 84) and fluoxetine (n = 447) were obtained and analysed. The demographic information, types of interaction, severity of the ADR, and the body systems affected (using the Anatomical Therapeutic Chemical classification system) were recorded for individual ADR cases. The majority of spontaneously reported ADRs for St. John's Wort and fluoxetine were concerning females aged 26-50 years (28.6%, 22.8%). The organ systems affected by ADRs to St John's Wort and fluoxetine have a similar profile, with the majority of cases affecting the central nervous system (45.2%, 61.7%). This result demonstrates that herbal preparations can result in ADRs similar to those of prescription medications. © 2015 Wiley Publishing Asia Pty Ltd.
Data-mining for detecting signals of adverse drug reactions of fluoxetine using the Korea Adverse Event Reporting System (KAERS) database.

PubMed

Kim, Seonji; Park, Kyounghoon; Kim, Mi-Sook; Yang, Bo Ram; Choi, Hyun Jin; Park, Byung-Joo

2017-10-01

Selective serotonin reuptake inhibitors (SSRIs) have become one of the most broadly used medications in psychiatry. Fluoxetine is the first representative antidepressant SSRI drug approved by the Food and Drug Administration (FDA) in 1987. Safety information on fluoxetine use alone was less reported than its combined use with other drugs. There were no published papers on adverse drug reactions (ADRs) of fluoxetine analyzing spontaneous adverse events reports. We detected signals of the adverse drug reactions of fluoxetine by data mining using the Korea Adverse Events Reporting System (KAERS) database. We defined signals in this study by the reporting odds ratios (ROR), proportional reporting ratios (PRR), and information components (IC) indices. The KAERS database included 860,224 AE reports, among which 866 reports contained fluoxetine. We compared the labels of fluoxetine among the United States, UK, Germany, France, China, and Korea. Some of the signals, including emotional lability, myositis, spinal stenosis, paradoxical drug reaction, drug dependence, extrapyramidal disorder, adrenal insufficiency, and intracranial hemorrhage, were not labeled in the six countries. In conclusion, we identified new signals that were not known at the time of market approval. However, certain factors should be required for signal evaluation, such as clinical significance, preventability, and causality of the detected signals. Copyright © 2017 Elsevier B.V. All rights reserved.
Maternal postpartum corticosterone and fluoxetine differentially affect adult male and female offspring on anxiety-like behavior, stress reactivity, and hippocampal neurogenesis.

PubMed

Gobinath, Aarthi R; Workman, Joanna L; Chow, Carmen; Lieblich, Stephanie E; Galea, Liisa A M

2016-02-01

Postpartum depression (PPD) affects approximately 15% of mothers, disrupts maternal care, and can represent a form of early life adversity for the developing offspring. Intriguingly, male and female offspring are differentially vulnerable to the effects of PPD. Antidepressants, such as fluoxetine, are commonly prescribed for treating PPD. However, fluoxetine can reach offspring via breast milk, raising serious concerns regarding the long-term consequences of infant exposure to fluoxetine. The goal of this study was to examine the long-term effects of maternal postpartum corticosterone (CORT, a model of postpartum stress/depression) and concurrent maternal postpartum fluoxetine on behavioral, endocrine, and neural measures in adult male and female offspring. Female Sprague-Dawley dams were treated daily with either CORT or oil and fluoxetine or saline from postnatal days 2-23, and offspring were weaned and left undisturbed until adulthood. Here we show that maternal postpartum fluoxetine increased anxiety-like behavior and impaired hypothalamic-pituitary-adrenal (HPA) axis negative feedback in adult male, but not female, offspring. Furthermore, maternal postpartum fluoxetine increased the density of immature neurons (doublecortin-expressing) in the hippocampus of adult male offspring but decreased the density of immature neurons in adult female offspring. Maternal postpartum CORT blunted HPA axis negative feedback in males and tended to increase density of immature neurons in males but decreased it in females. These results indicate that maternal postpartum CORT and fluoxetine can have long-lasting effects on anxiety-like behavior, HPA axis negative feedback, and adult hippocampal neurogenesis and that adult male and female offspring are differentially affected by these maternal manipulations. Copyright © 2015 Elsevier Ltd. All rights reserved.

Biochemical and locomotor responses of Carcinus maenas exposed to the serotonin reuptake inhibitor fluoxetine.

PubMed

Mesquita, Sofia Raquel; Guilhermino, Lúcia; Guimarães, Laura

2011-10-01

The aim of this study was to assess the effects of the widely used anti-depressant fluoxetine on behaviour (locomotion), moulting, neuromuscular transmission, energy production and anti-oxidant defences' efficiency of the epibenthic crab Carcinus maenas. Crabs were individually exposed to fluoxetine concentrations for 7d. Effects on locomotion were assessed at the end of the exposure using an open field test adapted to C. maenas in the present study. Tissue samples were later collected to evaluate fluoxetine effects on physiological functions using the activity of key enzymes and other parameters as biomarkers, namely: N-acetyl-β-glucosaminidase (NAGase) in the epidermis (moulting) and the hepatopancreas; cholinesterases (ChE) in muscle (neuromuscular cholinergic transmission); NADP(+)-dependent isocitrate dehydrogenase (IDH) and lactate dehydrogenease (LDH) in muscle (energy production); glutathione S-transferases (GST) in hepatopancreas (biotransformation and oxidative stress system); glutathione reductase (GR), and glutathione peroxidade (GPx), total glutathione levels (TG) and lipid peroxidation levels in the hepatopancreas (anti-oxidant defences and oxidative damage). Because no information on C. maenas NAGase activity was previously available, its variation during the moult cycle was also investigated. The results showed that locomotion was significantly increased at fluoxetine concentrations equal or above 120 μg L⁻¹, with animals spending more time moving, walking longer distances than controls. Levels of NAGase activity were found to vary in relation to C. maenas moult cycle, but no alterations were observed after exposure to fluoxetine. Significant increases in the activity of ChE, GST and GR enzymes, and the levels of TG were found, with a lowest observed effect concentration (LOEC) of 120 μg L⁻¹. Effects on locomotion were significantly and positively correlated to those induced on ChE activity. The results raise concern when hypothesising
Interstitial lung disease induced by fluoxetine: Systematic review of literature and analysis of Vigiaccess, Eudravigilance and a national pharmacovigilance database.

PubMed

Deidda, Arianna; Pisanu, Claudia; Micheletto, Laura; Bocchetta, Alberto; Del Zompo, Maria; Stochino, Maria Erminia

2017-06-01

We investigated a pulmonary adverse drug reaction possibly induced by fluoxetine, the Interstitial Lung Disease, by performing a systematic review of published case reports on this subject, a review of the World Health Organization VigiAccess database, of the European EudraVigilance database and of a national Pharmacovigilance database (Italian Pharmacovigilance Network). The research found a total of seven cases linking fluoxetine to Interstitial Lung Disease in the literature. 36 cases of interstitial lung disease related to fluoxetine were retrieved from the VigiAccess database (updated to July 2016), and 36 reports were found in EudraVigilance database (updated to June 2016). In the Italian Pharmacovigilance database (updated to August 2016), we found only one case of Interstitial Lung Disease, codified as "pulmonary disease". Our investigation shows that fluoxetine might be considered as a possible cause of Interstitial Lung Disease. In particular, although here we do not discuss the assessment of benefits and harms of fluoxetine, since this antidepressant is widely used, our review suggests that fluoxetine-induced Interstitial Lung Disease should be considered in patients with dyspnea, associated or not with dry cough, who are treated with this drug. An early withdrawn of fluoxetine could be useful to obtain a complete remission of this adverse drug reaction and special attention should be particularly devoted to long-term therapy, and to female and elderly patients. Although the spontaneous reporting system is affected by important limitations, drug post- marketing surveillance represents an important tool to evaluate the real world effectiveness and safety of drugs. Copyright © 2017 Elsevier Ltd. All rights reserved.
Association of regulatory TPH2 polymorphisms with higher reduction in depressive symptoms in children and adolescents treated with fluoxetine.

PubMed

Gassó, Patricia; Rodríguez, Natalia; Boloc, Daniel; Blázquez, Ana; Torres, Teresa; Gortat, Ana; Plana, Maria Teresa; Lafuente, Amalia; Mas, Sergi; Arnaiz, Joan Albert; Lázaro, Luisa

2017-07-03

Genetic variability related to the brain serotonergic system has a significant impact on both the susceptibility to psychiatric disorders, such as major depressive disorder (MDD), and the response to antidepressant drugs, such as fluoxetine. TPH2 is one of the most important serotonergic candidate genes in selective serotonin reuptake inhibitors (SSRIs) pharmacogenetic studies. The aim of the present study was to evaluate the influence of regulatory polymorphisms that are specifically located in human TPH2 transcription factor binding sites (TFBSs), and therefore could be functional by altering gene expression, on clinical improvement in children and adolescents treated with fluoxetine. The selection of SNPs was also based on their linkage disequilibrium with TPH2 rs4570625, a genetic variant with questionable functionality, which was previously associated with clinical response in our pediatric population. A total of 83 children and adolescents were clinically evaluated 12weeks after initiating antidepressant treatment with fluoxetine for the first time. Clinical improvement was assessed by reductions in depressive symptoms measured using the Children's Depression Inventory (CDI) scale. The polymorphisms rs11179002, rs60032326 and rs34517220 were, for the first time in the literature, significantly associated with higher clinical improvement. The strongest association was found for rs34517220. In particular, minor allele homozygotes showed higher score reductions on the CDI scale compared with the major allele carriers. Interestingly, this polymorphism is located in a human TPH2 TFBS for two relevant transcription factors in the serotoninergic neurons, Foxa1 and Foxa2, which together with the high level of significance found for this SNP, could indicate that rs34517220 is in fact the crucial functional genetic variant related to the fluoxetine response. These results provide new evidence for the role of regulatory genetic variants that could modulate human TPH2
The potential contributing effect of ketorolac and fluoxetine to a spinal epidural hematoma following a cervical interlaminar epidural steroid injection: a case report and narrative review.

PubMed

Chien, George C Chang; McCormick, Zack; Araujo, Marco; Candido, Kenneth D

2014-01-01

Cervical interlaminar epidural steroid injections (ESIs) are commonly performed as one part of a multi-modal analgesic regimen in the management of upper extremity radicular pain. Spinal epidural hematoma (SEH) is a rare complication with a reported incidence ranging from 1.38 in 10,000 to 1 in 190,000 epidurals. Current American Society of Regional Anesthesia (ASRA), American Society of Interventional Pain Physicians (ASIPP), and the International Spine Intervention Society (ISIS) recommendations are that non-steroidal anti-inflammatory drugs (NSAIDs) do not need to be withheld prior to epidural anesthesia. We report a case wherein intramuscular ketorolac and oral fluoxetine contributed to a SEH and tetraplegia following a cervical interlaminar (ESI). A 66 year-old woman with chronic renal insufficiency and neck pain radiating into her right upper extremity presented for evaluation and was deemed an appropriate CESI candidate. Cervical magnetic resonance imaging (MRI) revealed multi-level neuroforaminal stenosis and degenerative intervertebral discs. Utilizing a loss of resistance to saline technique, an 18-gauge Tuohy-type needle entered the epidural space at C6-7. After negative aspiration, 4 mL of saline with 80 mg of methyl-prednisolone was injected. Immediately thereafter, the patient reported significant spasmodic-type localized neck pain with no neurologic status changes. A decision was made to administer 30 mg intramuscular ketorolac as treatment for the spasmodic-type pain. En route home, she developed a sudden onset of acute tetraplegia. She was brought to the emergency department for evaluation including platelet and coagulation studies which were normal. MRI demonstrated an epidural hematoma extending from C5 to T7. She underwent a bilateral C5-T6 laminectomy with epidural hematoma evacuation and was discharged to an acute inpatient rehabilitation hospital. Chronic renal insufficiency, spinal stenosis, female gender, and increasing age have been
Fluoxetine for Autistic Behaviors (FAB trial): study protocol for a randomized controlled trial in children and adolescents with autism.

PubMed

Mouti, Anissa; Reddihough, Dinah; Marraffa, Catherine; Hazell, Philip; Wray, John; Lee, Katherine; Kohn, Michael

2014-06-16

Serotonin reuptake inhibitors (SSRIs) are commonly prescribed off-label for children with autism. To date, clinical trials examining the use of SSRIs in autism have been limited by small sample sizes and inconclusive results. The efficacy and safety of SSRIs for moderating autistic behaviors is yet to be adequately examined to provide evidence to support current clinical practice. The aim of the Fluoxetine for Autistic Behaviors (FAB) study is to determine the efficacy and safety of low dose fluoxetine compared with placebo, for reducing the frequency and severity of repetitive stereotypic behaviors in children and adolescents with an autism spectrum disorder (ASD). The relationship between the effectiveness of fluoxetine treatment and serotonin transporter genotype will also be explored. The FAB study is a multicenter, double-blinded, randomized controlled trial, funded by the Australian Government's National Health and Medical Research Council (NHMRC) grant. Participants will be aged between 7.5 and 17 years with a confirmed diagnosis of ASD. Eligible participants will be randomized to either placebo or fluoxetine for a 16-week period. Medication will be titrated over the first four weeks. Reponses to medication will be monitored fortnightly using the Clinical Global Impressions Scale (CGI). The primary outcome measure is the Children's Yale-Brown Obsessive Compulsive Scale-Modified for Pervasive Developmental Disorders (CYBOCS-PDD), administered at baseline and 16 weeks. Secondary outcome measures include the Aberrant Behaviour Scale (ABC), the Spence Children's Anxiety Scale Parent Report (SCAS-P), and the Repetitive Behaviors Scale (RBS-R), measured at baseline and 16 weeks. Participants will be invited to undergo genetic testing for SLC6A4 allele variants using a cheek swab. Continuous outcomes, including the primary outcome will be compared between the active and placebo groups using unadjusted linear regression. Binary outcomes will be compared using
The panicolytic-like effect of fluoxetine in the elevated T-maze is mediated by serotonin-induced activation of endogenous opioids in the dorsal periaqueductal grey.

PubMed

Roncon, Camila M; Biesdorf, Carla; Santana, Rosangela G; Zangrossi, Hélio; Graeff, Frederico G; Audi, Elisabeth A

2012-04-01

Serotonin (5-HT), opioids and the dorsal periaqueductal grey (DPAG) have been implicated in the pathophysiology of panic disorder. In order to study 5-HT-opioid interaction, the opioid antagonist naloxone was injected either systemically (1 mg/kg, i.p.) or intra-DPAG (0.2 μg/0.5 μL) to assess its interference with the effect of chronic fluoxetine (10 mg/kg, i.p., daily for 21 days) or of intra-DPAG 5-HT (8 μg/0.5 μL). Drug effects were measured in the one-escape task of the rat elevated T-maze, an animal model of panic. Pretreatment with systemic naloxone antagonized the lengthening of escape latency caused by chronic fluoxetine, considered a panicolytic-like effect that parallels the drug's therapeutic response in the clinics. Pretreatment with naloxone injected intra-DPAG antagonized both the panicolytic effect of chronic fluoxetine as well as that of 5-HT injected intra-DPAG. Neither the performance of the inhibitory avoidance task in the elevated T-maze, a model of generalized anxiety nor locomotion measured in a circular arena was affected by the above drug treatments. These results indicate that the panicolytic effect of fluoxetine is mediated by endogenous opioids that are activated by 5-HT in the DPAG. They also allow reconciliation between the serotonergic and opioidergic hypotheses of panic disorder pathophysiology.
Chronic Fluoxetine Induces Activity Changes in Recovery From Poststroke Anxiety, Depression, and Cognitive Impairment.

PubMed

Vahid-Ansari, Faranak; Albert, Paul R

2018-01-01

Poststroke depression (PSD) is a common outcome of stroke that limits recovery and is only partially responsive to chronic antidepressant treatment. In order to elucidate changes in the cortical-limbic circuitry associated with PSD and its treatment, we examined a novel mouse model of persistent PSD. Focal endothelin-1-induced ischemia of the left medial prefrontal cortex (mPFC) in male C57BL6 mice resulted in a chronic anxiety and depression phenotype. Here, we show severe cognitive impairment in spatial learning and memory in the stroke mice. The behavioral and cognitive phenotypes were reversed by chronic (4-week) treatment with fluoxetine, alone or with voluntary exercise (free-running wheel), but not by exercise alone. To assess chronic cellular activation, FosB + cells were co-labeled for markers of glutamate/pyramidal (VGluT1-3/CaMKIIα), γ-aminobutyric acid (GAD67), and serotonin (TPH). At 6 weeks poststroke versus sham (or 4 days poststroke), left mPFC stroke induced widespread FosB activation, more on the right (contralesional) than on the left side. Stroke activated glutamate cells of the mPFC, nucleus accumbens, amygdala, hippocampus, and raphe serotonin neurons. Chronic fluoxetine balanced bilateral neuronal activity, reducing total FosB and FosB/CamKII + cells (mPFC, nucleus accumbens), and unlike exercise, increasing FosB/GAD67 + cells (septum, amygdala) or both (hippocampus, raphe). In summary, chronic antidepressant but not exercise mediates recovery in this unilateral ischemic PSD model that is associated with region-specific reversal of stroke-induced pyramidal cell hyperactivity and increase in γ-aminobutyric acidergic activity. Targeted brain stimulation to restore brain activity could provide a rational approach for treating clinical PSD.
Transient postnatal fluoxetine decreases brain concentrations of 20-HETE and 15-epi-LXA4, arachidonic acid metabolites in adult mice.

PubMed

Yuan, Zhi-Xin; Rapoport, Stanley I

2015-10-01

Transient postnatal exposure of rodents to the selective serotonin (5-HT) reuptake inhibitor (SSRI) fluoxetine alters behavior and brain 5-HT neurotransmission during adulthood, and also reduces brain arachidonic (ARA) metabolic consumption and protein level of the ARA metabolizing enzyme, cytochrome P4504A (CYP4A). Brain 20-hydroxyeicosatetraenoic acid (20-HETE), converted by CYP4A from ARA, will be reduced in adult mice treated transiently and postnatally with fluoxetine. Male mice pups were injected i.p. daily with fluoxetine (10mg/kg) or saline during P4-P21. At P90 their brain was high-energy microwaved and analyzed for 20-HETE and six other ARA metabolites by enzyme immunoassay. Postnatal fluoxetine vs. saline significantly decreased brain concentrations of 20-HETE (-70.3%) and 15-epi-lipoxin A4 (-60%) in adult mice, but did not change other eicosanoid concentrations. Behavioral changes in adult mice treated postnatally with fluoxetine may be related to reduced brain ARA metabolism involving CYP4A and 20-HETE formation. Published by Elsevier Ltd.
Robust presynaptic serotonin 5-HT1B receptor inhibition of the striatonigral output and its sensitization by chronic fluoxetine treatment

PubMed Central

Ding, Shengyuan; Li, Li

2015-01-01

The striatonigral projection is a striatal output pathway critical to motor control, cognition, and emotion regulation. Its axon terminals in the substantia nigra pars reticulata (SNr) express a high level of serotonin (5-HT) type 1B receptors (5-HT1BRs), whereas the SNr also receives an intense 5-HT innervation that expresses 5-HT transporters, providing an anatomic substrate for 5-HT and selective 5-HT reuptake inhibitor (SSRI)-based antidepressant treatment to regulate the striatonigral output. In this article we show that 5-HT, by activating presynaptic 5-HT1BRs on the striatonigral axon terminals, potently inhibited the striatonigral GABA output, as reflected in the reduction of the striatonigral inhibitory postsynaptic currents in SNr GABA neurons. Functionally, 5-HT1BR agonism reduced the striatonigral GABA output-induced pause of the spontaneous high-frequency firing in SNr GABA neurons. Equally important, chronic SSRI treatment with fluoxetine enhanced this presynaptic 5-HT1BR-mediated pause reduction in SNr GABA neurons. Taken together, these results indicate that activation of the 5-HT1BRs on the striatonigral axon terminals can limit the motor-promoting GABA output. Furthermore, in contrast to the desensitization of 5-HT1 autoreceptors, chronic SSRI-based antidepressant treatment sensitizes this presynaptic 5-HT1BR-mediated effect in the SNr, a novel cellular mechanism that alters the striatonigral information transfer, potentially contributing to the behavioral effects of chronic SSRI treatment. PMID:25787955
Adolescence fluoxetine increases serotonergic activity in the raphe-hippocampus axis and improves depression-like behaviors in female rats that experienced neonatal maternal separation.

PubMed

Yoo, Sang Bae; Kim, Bom-Taeck; Kim, Jin Young; Ryu, Vitaly; Kang, Dong-Won; Lee, Jong-Ho; Jahng, Jeong Won

2013-06-01

This study was conducted to examine if fluoxetine, a selective 5-hydroxytryptamine (5-HT) reuptake inhibitor, would reverse adverse behavioral effects of neonatal maternal separation in female rats. Sprague-Dawley pups were separated from dam daily for 3h during postnatal day (PND) 1-14 (maternal separation; MS) or left undisturbed (non-handled; NH). Female NH and MS pups received intraperitoneal injection of fluoxetine (10mg/kg) or vehicle daily from PND 35 until the end of the whole experimental period. Rats were either subjected to behavioral tests during PND 44-54, or sacrificed for neurochemical analyses during PND 43-45. Daily food intake and weight gain of both NH and MS pups were suppressed by fluoxetine, with greater effects in MS pups. MS experience increased immobility and decrease swimming in forced swim test. Swimming was increased, although immobility was not significantly decreased, in MS females by adolescence fluoxetine. However, adolescence fluoxetine increased immobility during forced swim test and decreased time spent in open arms during elevated plus maze test in NH females. Fluoxetine normalized MS-induced decrease of the raphe 5-HT levels and increased 5-HT metabolism in the hippocampus in MS females, and increased the hypothalamic 5-HT both in NH and MS. Fluoxetine decreased the raphe 5-HT and increased the plasma corticosterone in NH females. Results suggest that decreased 5-HTergic activity in the raphe nucleus is implicated in the pathophysiology of depression-like behaviors, and increased 5-HTergic activities in the raphe-hippocampus axis may be a part of anti-depressant efficacy of fluoxetine, in MS females. Also, an extra-hypothalamic 5-HTergic activity may contribute to the increased anorectic efficacy of fluoxetine in MS females. Additionally, decreased 5-HT in the raphe and elevated plasma corticosterone may be related with fluoxetine-induced depression- and/or anxiety-like behaviors in NH females. Copyright © 2012 Elsevier Ltd
Adult Acute Myeloid Leukemia Treatment (PDQ®)—Health Professional Version

Cancer.gov

Acute myeloid leukemia (AML; also called acute myelogenous leukemia, acute nonlymphocytic leukemia) treatment advances have resulted in substantially improved CR rates. Cytogenetic analysis helps predict outcomes of treatment which includes chemotherapy, radiation, and stem cell transplant. Get detailed information about AML in this clinician summary.
Treatment of Depression in Adolescents with Cognitive Behavior Therapy and Medications: A Commentary on the TADS Project

ERIC Educational Resources Information Center

Hollon, Steven D.; Garber, Judy; Shelton, Richard C.

2005-01-01

This article reviews and comments on the recent Treatment for Adolescents With Depression Study (TADS) that found that cognitive behavior therapy (CBT) was less efficacious than fluoxetine alone and no more efficacious than pill placebo in the treatment of depression in adolescents. Adding CBT to fluoxetine, however, improved treatment response in…
Social learning requires plasticity enhanced by fluoxetine through prefrontal Bdnf-TrkB signaling to limit aggression induced by post-weaning social isolation

PubMed Central

Umemori, Juzoh; Tóth, Máté; Biró, László; Miskolczi, Christina; Balázsfi, Diána; Zelena, Dóra; Castrén, Eero

2017-01-01

Escalated or abnormal aggression induced by early adverse experiences is a growing issue of social concern and urges the development of effective treatment strategies. Here we report that synergistic interactions between psychosocial and biological factors specifically ameliorate escalated aggression induced by early adverse experiences. Rats reared in isolation from weaning until early adulthood showed abnormal forms of aggression and social deficits that were temporarily ameliorated by re-socialization, but aggression again escalated in a novel environment. We demonstrate that when re-socialization was combined with the antidepressant fluoxetine, which has been shown to reactivate juvenile-like state of plasticity, escalated aggression was greatly attenuated, while neither treatment alone was effective. Early isolation induced a permanent, re-socialization resistant reduction in Bdnf expression in the amygdala and the infralimbic cortex. Only the combined treatment of fluoxetine and re-socialization was able to recover Bdnf expression via epigenetic regulation. Moreover, the behavior improvement after the combined treatment was dependent on TrkB activity. Combined treatment specifically strengthened the input from the ventral hippocampus to the mPFC suggesting that this pathway is an important mediator of the beneficial behavioral effects of the combined psychosocial and pharmacological treatment of abnormal aggression. Our findings suggest that synergy between pharmacological induction of plasticity and psychosocial rehabilitation could enhance the efficacy of therapies for pathological aggression. PMID:28685757
Total synthesis of fluoxetine and duloxetine through an in situ imine formation/borylation/transimination and reduction approach.

PubMed

Calow, Adam D J; Fernández, Elena; Whiting, Andrew

2014-08-28

We report efficient, catalytic, asymmetric total syntheses of both (R)-fluoxetine and (S)-duloxetine from α,β-unsaturated aldehydes conducting five sequential one-pot steps (imine formation/copper mediated β-borylation/transimination/reduction/oxidation) followed by the specific ether group formation which deliver the desired products (R)-fluoxetine in 45% yield (96% ee) and (S)-duloxetine in 47% yield (94% ee).
Graphene/graphite paste electrode incorporated with molecularly imprinted polymer nanoparticles as a novel sensor for differential pulse voltammetry determination of fluoxetine.

PubMed

Alizadeh, Taher; Azizi, Sorour

2016-07-15

Molecularly imprinted polymer (MIP) nanoparticles including highly selective recognition sites for fluoxetine were synthesized, utilizing precipitation polymerization. Methacrylic acid and vinyl benzene were used as functional monomers. Ethylene glycol dimethacrylate was used as cross-linker agent. The obtained polymeric nanoparticles were incorporated with carbon paste electrode (CPE) in order to construct a fluoxetine selective sensor. The response of the MIP-CP electrode to fluoxetine was remarkably higher than the electrode, modified with the non-imprinted polymer, indicating the excellent efficiency of the MIP sites for target molecule recognition. It was found that the addition of a little amount of graphene, synthesized via modified hummer's method, to the MIP-CP resulted in considerable enhancement in the sensitivity of the electrode to fluoxetine. Also, the style of electrode components mixing, before carbon paste preparation, was demonstrated to be influential factor in the electrode response. Some parameters, affecting sensor response, were optimized and then a calibration curve was plotted. A dynamic linear range of 6×10(-9)-1.0×10(-7)molL(-1) was obtained. The detection limit of the sensor was calculated equal to 2.8×10(-9)molL(-1) (3Sb/m). This sensor was used successfully for fluoxetine determination in the spiked plasma samples as well as fluoxetine capsules. Copyright © 2016 Elsevier B.V. All rights reserved.
Fluoxetine Treatment of Alcoholic Perpetrators of Domestic Violence: A 12-Week, Double-Blind, Randomized, Placebo-Controlled Intervention Study

PubMed Central

George, David T.; Phillips, Monte J.; Lifshitz, Mariel; Lionetti, Thomas A.; Spero, David E.; Ghassemzedeh, Niloofar; Doty, Linda; Umhau, John C.; Rawlings, Robert R.

2010-01-01

Objective Behaviorally based therapies for the treatment of perpetrators who initiate intimate partner violence (IPV) have generally shown minimal therapeutic efficacy. To explore a new treatment approach for IPV, we examined the effects of a selective serotonin reuptake inhibitor on the irritability subscale score of the Modified Overt Aggression Scale. This score served as a surrogate marker for the anger and physical aggression that characterize perpetrators of IPV. Method A 12-week, double-blind, randomized, placebo-controlled intervention study employing fluoxetine, alcohol treatment, and cognitive-behavioral therapy was performed. Sixty (46 men) non–court-mandated, DSM-IV–diagnosed alcoholic perpetrators of IPV with a history of at least 2 episodes of IPV in the year prior to participation in the study were evaluated. The primary outcome measure was the score on the irritability subscale of the Modified Overt Aggression Scale. Secondary measures included anxiety, depression, and ratings by the perpetrator's spouse/significant other. The study was conducted from January 2002 through December 2007. Results A repeated-measures analysis of variance using the irritability subscale scores obtained from perpetrators who completed the 12-week study (n = 24) showed a significant drug effect (F1,21 = 12.09, P = .002). Last observation carried forward (F1,32 = 4.24, P = .048) as well as intent-to-treat analysis (F1,54 = 5.0, P = .034) also showed a significant drug effect. Spouses'/significant others' physical and nonphysical Partner Abuse Scale ratings showed a significant reduction of abuse over time (F1,11 = 10.2, P = .009 and F1,11 = 24.2, P = .0005, respectively). Conclusion This is the first controlled study to show that a pharmacologic intervention employing a selective serotonin reuptake inhibitor, in conjunction with alcohol treatment and cognitive-behavioral therapy, can reduce measures of anger and physical aggression in alcoholic perpetrators of IPV
Fluoxetine maintains a state of heightened responsiveness to motor training early after stroke in a mouse model

PubMed Central

Ng, Kwan; Gibson, Ellen M.; Hubbard, Robert; Yang, Juemin; Caffo, Brian; O’Brien, Richard; Krakauer, John W.; Zeiler, Steven R.

2016-01-01

Background and purpose Data from both humans and animal models suggest that most recovery from motor impairment occurs in a sensitive period that lasts only weeks after stroke and is mediated in part by an increased responsiveness to training. Here we used a mouse model of focal cortical stroke to test two hypotheses. First we investigated if responsiveness to training decreases over time after stroke. Second, we tested whether fluoxetine, which can influence synaptic plasticity and stroke recovery, can prolong the period over which large training-related gains can be elicited after stroke. Methods Mice were trained to perform a skilled prehension task to an asymptotic level of performance after which they underwent stroke induction in the caudal forelimb area (CFA). The mice were then retrained after a 1-day or 7-day delay with and without fluoxetine. Results Recovery of prehension after a CFA stroke was complete if training was initiated one day after stroke but incomplete if it was delayed by 7 days. In contrast, if fluoxetine was administered at 24 hours after stroke, then complete recovery of prehension was observed even with the 7-day training delay. Fluoxetine appeared to mediate its beneficial effect by reducing inhibitory interneuron expression in intact premotor cortex rather than through effects on infarct volume or cell death. Conclusions There is a gradient of diminishing responsiveness to motor training over the first week after stroke. Fluoxetine can overcome this gradient and maintain maximal levels of responsiveness to training even 7 days after stroke. PMID:26294676
Fluoxetine Maintains a State of Heightened Responsiveness to Motor Training Early After Stroke in a Mouse Model.

PubMed

Ng, Kwan L; Gibson, Ellen M; Hubbard, Robert; Yang, Juemin; Caffo, Brian; O'Brien, Richard J; Krakauer, John W; Zeiler, Steven R

2015-10-01

Data from both humans and animal models suggest that most recovery from motor impairment after stroke occurs in a sensitive period that lasts only weeks and is mediated, in part, by an increased responsiveness to training. Here, we used a mouse model of focal cortical stroke to test 2 hypotheses. First, we investigated whether responsiveness to training decreases over time after stroke. Second, we tested whether fluoxetine, which can influence synaptic plasticity and stroke recovery, can prolong the period over which large training-related gains can be elicited after stroke. Mice were trained to perform a skilled prehension task to an asymptotic level of performance after which they underwent stroke induction in the caudal forelimb area. The mice were then retrained after a 1- or 7-day delay with and without fluoxetine. Recovery of prehension after a caudal forelimb area stroke was complete if training was initiated 1 day after stroke but incomplete if it was delayed by 7 days. In contrast, if fluoxetine was administered at 24 hours after stroke, then complete recovery of prehension was observed even with the 7-day training delay. Fluoxetine seemed to mediate its beneficial effect by reducing inhibitory interneuron expression in intact premotor cortex rather than through effects on infarct volume or cell death. There is a gradient of diminishing responsiveness to motor training over the first week after stroke. Fluoxetine can overcome this gradient and maintain maximal levels of responsiveness to training even 7 days after stroke. © 2015 American Heart Association, Inc.
Adult Acute Lymphoblastic Leukemia Treatment (PDQ®)—Health Professional Version

Cancer.gov

Adult Acute Lymphoblastic Leukemia (ALL; also called acute lymphocytic leukemia) is an aggressive cancer that can progress quickly without treatment. Treatments include chemotherapy, radiation therapy, stem cell transplant, and targeted therapy. Get detailed information about the molecular genetics, prognosis, and treatment of ALL in this clinician summary.
Effect of addition of yohimbine (alpha-2-receptor antagonist) to the antidepressant activity of fluoxetine or venlafaxine in the mouse forced swim test.

PubMed

Dhir, Ashish; Kulkarni, S K

2007-01-01

Studies have suggested that alpha(2)-adrenoceptors strongly affect monoaminergic neurotransmission by enhancing not only noradrenergic but also serotonergic firing rates. With this background in mind, the present study was undertaken to monitor the effect of addition of yohimbine (alpha(2)-adrenoceptor antagonist) to the effect of fluoxetine (selective serotonin reuptake inhibitor) or venlafaxine (dual reuptake inhibitors of both serotonin and norepinephrine) in Porsolt's forced swim test (FST) using male Laca strain mice. The immobility period was recorded in mouse FST during a 6-min period. Different doses of fluoxetine or venlafaxine were administered 30 min before exposing the animals to the test procedure. In the combination study, yohimbine (2 mg/kg i.p.) was administered 15 min before the administration of different doses of fluoxetine or venlafaxine. Fluoxetine (5, 10, 20 and 40 mg/kg) [F = 28.352] or venlafaxine (2, 4, 8 and 16 mg/kg) [F = 17.842] dose-dependently inhibited the immobility period in mice. Addition of yohimbine (2 mg/kg i.p.) potentiated the antidepressant action of fluoxetine or venlafaxine in mouse FST as the animals showed a decrease in the immobility period compared to the fluoxetine or venlafaxine per se group, respectively. The present study not only demonstrated the association of alpha(2)-receptors in the antidepressant effect of fluoxetine or venlafaxine, but also supports its adjuvant therapy with other antidepressant drugs. (c) 2007 S. Karger AG, Basel.

Home treatment for acute psychiatric illness.

PubMed

Dean, C; Gadd, E M

1990-11-03

To determine the factors influencing the successful outcome of community treatment for severe acute psychiatric illnesses that are traditionally treated in hospital. All patients from a single electoral ward who were either admitted to hospital or treated at home over a two year period (1 October 1987 to 30 September 1989) were included in the study and their case notes audited. The second year of the study is reported. Electoral ward of Sparkbrook, Birmingham. 99 Patients aged 16-65 with severe acute psychiatric illness. 65 Patients were managed by home treatment alone; 34 required admission to hospital. The location of treatment was significantly (all p less than 0.05) influenced by social characteristics of the patients (marital state, age (in men), ethnicity, and living alone) and by characteristics of the referral (occurring out of hours; assessment taking place at hospital or police station). DSM-III-R diagnosis was more weakly associated with outcome. Violence during the episode was significantly related to admission, although deliberate self harm was not. Home treatment is feasible for most patients with acute psychiatric illness. A 24 hour on call assessment service increases the likelihood of success because admission is determined more strongly by social characteristics of the patient and the referral than by illness factors. Admission will still be required for some patients. A locally based mental health resource centre, a 24 hour on call service, an open referral system, and an active follow up policy increase the effectiveness of a home treatment service.
Home treatment for acute psychiatric illness.

PubMed Central

Dean, C; Gadd, E M

1990-01-01

OBJECTIVE--To determine the factors influencing the successful outcome of community treatment for severe acute psychiatric illnesses that are traditionally treated in hospital. DESIGN--All patients from a single electoral ward who were either admitted to hospital or treated at home over a two year period (1 October 1987 to 30 September 1989) were included in the study and their case notes audited. The second year of the study is reported. SETTING--Electoral ward of Sparkbrook, Birmingham. SUBJECTS--99 Patients aged 16-65 with severe acute psychiatric illness. RESULTS--65 Patients were managed by home treatment alone; 34 required admission to hospital. The location of treatment was significantly (all p less than 0.05) influenced by social characteristics of the patients (marital state, age (in men), ethnicity, and living alone) and by characteristics of the referral (occurring out of hours; assessment taking place at hospital or police station). DSM-III-R diagnosis was more weakly associated with outcome. Violence during the episode was significantly related to admission, although deliberate self harm was not. CONCLUSIONS--Home treatment is feasible for most patients with acute psychiatric illness. A 24 hour on call assessment service increases the likelihood of success because admission is determined more strongly by social characteristics of the patient and the referral than by illness factors. Admission will still be required for some patients. A locally based mental health resource centre, a 24 hour on call service, an open referral system, and an active follow up policy increase the effectiveness of a home treatment service. PMID:2249049
Fluoxetine induces lean phenotype in rat by increasing the brown/white adipose tissue ratio and UCP1 expression.

PubMed

da Silva, A I; Braz, G R F; Pedroza, A A; Nascimento, L; Freitas, C M; Ferreira, D J S; Manhães de Castro, R; Lagranha, C J

2015-08-01

The serotonergic system plays a crucial role in the energy balance regulation. Energy balance is mediated by food intake and caloric expenditure. Thus, the present study investigated the mechanisms that might be associated with fluoxetine treatment-induced weight reduction. Wistar male rat pups received daily injections with subcutaneous fluoxetine (Fx-group) or vehicle solution (Ct-group) from day 1 until 21 days of age. Several analyses were conducted to verify the involvement of mitochondria in weight reduction. We found that body weight in the Fx-group was lower compared to control. In association to lower fat mass in the Fx-group (25%). Neither neonatal caloric intake nor food intake reveals significant differences. Evaluating caloric expenditure (locomotor activity and temperature after stimulus), we did not observe differences in locomotor activity. However, we observed that the Fx group had a higher capacity to maintain body temperature in a cold environment compared with the Ct-group. Since brown adipose tissue-(BAT) is specialized for heat production and the rate of heat production is related to mitochondrial function, we found that Fx-treatment increases respiration by 36%, although after addition of GDP respiration returned to Ct-levels. Examining ROS production we observe that Fx-group produced less ROS than control group. Evaluating uncoupling protein (UCP) expression we found that Fx-treatment increases the expression by 23%. Taken together, our results suggest that modulation of serotonin system results in positive modulation of UCP and mitochondrial bioenergetics in brown fat tissue.
Pharmacological evidence for the mediation of the panicolytic effect of fluoxetine by dorsal periaqueductal gray matter μ-opioid receptors.

PubMed

Roncon, Camila Marroni; Almada, Rafael Carvalho; Maraschin, Jhonatan Christian; Audi, Elisabeth Aparecida; Zangrossi, Hélio; Graeff, Frederico Guilherme; Coimbra, Norberto Cysne

2015-12-01

Previously reported results have shown that the inhibitory effect of fluoxetine on escape behavior, interpreted as a panicolytic-like effect, is blocked by pretreatment with either the opioid receptor antagonist naloxone or the 5-HT1A receptor (5-HT1A-R) antagonist WAY100635 via injection into the dorsal periaqueductal gray matter (dPAG). Additionally, reported evidence indicates that the μ-opioid receptor (MOR) interacts with the 5-HT1A-R in the dPAG. In the present work, pretreatment of the dPAG with the selective MOR blocker CTOP antagonized the anti-escape effect of chronic fluoxetine (10 mg/kg, i.p., daily, for 21 days), as measured in the elevated T-maze (ETM) test, indicating mediation of this effect by the MOR. In addition, the combined administration of sub-effective doses of the selective MOR agonist DAMGO (intra-dPAG) and sub-effective doses of chronic as well as subchronic (7 days) fluoxetine increased avoidance and escape latencies, suggesting that the activation of MORs may facilitate and accelerate the effects of fluoxetine. The current observation that MORs located in the dPAG mediate the anti-escape effect of fluoxetine may open new perspectives for the development of more efficient and fast-acting panic-alleviating drugs. Copyright © 2015 Elsevier Ltd. All rights reserved.
Subacute administration of fluoxetine prevents short-term brain hypometabolism and reduces brain damage markers induced by the lithium-pilocarpine model of epilepsy in rats.

PubMed

Shiha, Ahmed Anis; de Cristóbal, Javier; Delgado, Mercedes; Fernández de la Rosa, Rubén; Bascuñana, Pablo; Pozo, Miguel A; García-García, Luis

2015-02-01

The role of serotonin (5-hydroxytryptamine; 5-HT) in epileptogenesis still remains controversial. In this regard, it has been reported that serotonergic drugs can alter epileptogenesis in opposite ways. The main objective of this work was to investigate the effect of the selective 5-HT selective reuptake inhibitor (SSRI) fluoxetine administered subacutely (10mg/kg/day×7 days) on the eventual metabolic impairment induced by the lithium-pilocarpine model of epilepsy in rats. In vivo 2-deoxy-2-[(18)F]fluoro-d-glucose ([(18)F] FDG) positron emission tomography (PET) was performed to assess the brain glucose metabolic activity on days 3 and 30 after the insult. In addition, at the end of the experiment (day 33), several histochemical and neurochemical assessments were performed for checking the neuronal functioning and integrity. Three days after the insult, a marked reduction of [(18)F] FDG uptake (about 30% according to the brain region) was found in all brain areas studied. When evaluated on day 30, although a hypometabolism tendency was observed, no statistically significant reduction was present in any region analyzed. In addition, lithium-pilocarpine administration was associated with medium-term hippocampal and cortical damage, since it induced neurodegeneration, glial activation and augmented caspase-9 expression. Regarding the effect of fluoxetine, subacute treatment with this SSRI did not significantly reduce the mortality rate observed after pilocarpine-induced seizures. However, fluoxetine did prevent not only the short-term metabolic impairment, but also the aforementioned signs of neuronal damage in surviving animals to lithium-pilocarpine protocol. Finally, fluoxetine increased the density of GABAA receptor both at the level of the dentate gyrus and CA1-CA2 regions in pilocarpine-treated animals. Overall, our data suggest a protective role for fluoxetine against pilocarpine-induced brain damage. Moreover, this action may be associated with an increase of
Routes of uptake of diclofenac, fluoxetine, and triclosan into sediment-dwelling worms.

PubMed

Karlsson, Maja V; Marshall, Stuart; Gouin, Todd; Boxall, Alistair B A

2016-04-01

The present study investigated the route and degree of uptake of 2 ionizable pharmaceuticals (diclofenac and fluoxetine) and 1 ionizable compound used in personal care products (triclosan) into the sediment-dwelling worm Lumbriculus variegatus. Studies were done on complete worms ("feeding") and worms where the head was absent ("nonfeeding") using (14) C-labeled ingredients. Biota sediment accumulation factors (BSAF), based on uptake of (14) C, for feeding worms increased in the order fluoxetine (0.3) < diclofenac (0.5) < triclosan (9), which is correlated with a corresponding increase in log octanol-water partition coefficient. Biota sediment accumulation factor estimates are representative of maximum values because the degree of biotransformation in the worms was not quantified. Although no significant differences were seen between the uptake of diclofenac and that of fluoxetine in feeding and nonfeeding worms, uptake of the more hydrophobic antimicrobial, triclosan, into the feeding worms was significantly greater than that in the nonfeeding worms, with the 48-h BSAF for feeding worms being 36% higher than that for the nonfeeding worms. The results imply that dietary uptake contributes to the uptake of triclosan, which may be a result of the high hydrophobicity of the compound. Models that estimate exposure of ionizable substances may need to consider uptake from both the water column and food, particularly when assessing risks from dynamic exposures to organic contaminants. © 2015 SETAC.
Differential weight restoration on olanzapine versus fluoxetine in identical twins with anorexia nervosa.

PubMed

Duvvuri, Vikas; Cromley, Taya; Klabunde, Megan; Boutelle, Kerri; Kaye, Walter H

2012-03-01

No studies have compared the response to selective serotonin reuptake inhibitors and atypical antipsychotics in anorexia nervosa. This case study examines such a comparison. This report describes a case of 12-year-old identical twins with anorexia nervosa, one of whom was treated with olanzapine and the other with fluoxetine, while undergoing family therapy. Twin A treated with fluoxetine went from 75 to 84.4% ideal body weight, while Twin B treated with olanzapine went from 72 to 99.9% ideal body weight over the course of 9 months. This case supports the need for adequately powered, controlled clinical trials to test the efficacy of olanzapine in adolescents presenting with anorexia nervosa. Copyright © 2011 Wiley Periodicals, Inc.
Chronic administration of fluoxetine or clozapine induces oxidative stress in rat liver: a histopathological study.

PubMed

Zlatković, Jelena; Todorović, Nevena; Tomanović, Nada; Bošković, Maja; Djordjević, Snežana; Lazarević-Pašti, Tamara; Bernardi, Rick E; Djurdjević, Aleksandra; Filipović, Dragana

2014-08-01

Chronic exposure to stress contributes to the etiology of mood disorders, and the liver as a target organ of antidepressant and antipsychotic drug metabolism is vulnerable to drug-induced toxicity. We investigated the effects of chronic administration of fluoxetine (15mg/kg/day) or clozapine (20mg/kg/day) on liver injury via the measurement of liver enzymes, oxidative stress and histopathology in rats exposed to chronic social isolation (21days), an animal model of depression, and controls. The activity of serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST), the liver content of carbonyl groups, malonyldialdehyde (MDA), reduced glutathione (GSH), cytosolic glutathione S-transferase (GST) and nitric oxide (NO) metabolites were determined. We also characterized nuclear factor-κB (NF-κB), cyclooxygenase-2 (COX-2) and CuZn-superoxide dismutase (CuZnSOD) protein expression as well as histopathological changes. Increased serum ALT activity in chronically-isolated and control animals treated with both drugs was found while increased AST activity was observed only in fluoxetine-treated rats (chronically-isolated and controls). Increased carbonyl content, MDA, GST activity and decreased GSH levels in drug-treated controls/chronically-isolated animals suggest a link between drugs and hepatic oxidative stress. Increased NO levels associated with NF-κB activation and the concomitant increased COX-2 expression together with compromised CuZnSOD expression in clozapine-treated chronically-isolated rats likely reinforce oxidative stress, observed by increased lipid peroxidation and GSH depletion. In contrast, fluoxetine reduced NO levels in chronically-isolated rats. Isolation induced oxidative stress but histological changes were similar to those observed in vehicle-treated controls. Chronic administration of fluoxetine in both chronically-isolated and control animals resulted in more or less normal hepatic architecture, while clozapine in both groups
Fluoxetine effects on molecular, cellular and behavioral endophenotypes of depression are driven by the living environment.

PubMed

Alboni, S; van Dijk, R M; Poggini, S; Milior, G; Perrotta, M; Drenth, T; Brunello, N; Wolfer, D P; Limatola, C; Amrein, I; Cirulli, F; Maggi, L; Branchi, I

2017-04-01

Selective serotonin reuptake inhibitors (SSRIs) represent the most common treatment for major depression. However, their efficacy is variable and incomplete. In order to elucidate the cause of such incomplete efficacy, we explored the hypothesis positing that SSRIs may not affect mood per se but, by enhancing neural plasticity, render the individual more susceptible to the influence of the environment. Consequently, SSRI administration in a favorable environment promotes a reduction of symptoms, whereas in a stressful environment leads to a worse prognosis. To test such hypothesis, we exposed C57BL/6 mice to chronic stress in order to induce a depression-like phenotype and, subsequently, to fluoxetine treatment (21 days), while being exposed to either an enriched or a stressful condition. We measured the most commonly investigated molecular, cellular and behavioral endophenotypes of depression and SSRI outcome, including depression-like behavior, neurogenesis, brain-derived neurotrophic factor levels, hypothalamic-pituitary-adrenal axis activity and long-term potentiation. Results showed that, in line with our hypothesis, the endophenotypes investigated were affected by the treatment according to the quality of the living environment. In particular, mice treated with fluoxetine in an enriched condition overall improved their depression-like phenotype compared with controls, whereas those treated in a stressful condition showed a distinct worsening. Our findings suggest that the effects of SSRI on the depression- like phenotype is not determined by the drug per se but is induced by the drug and driven by the environment. These findings may be helpful to explain variable effects of SSRI found in clinical practice and to device strategies aimed at enhancing their efficacy by means of controlling environmental conditions.
Fluoxetine increases the activity of the ERK-CREB signal system and alleviates the depressive-like behavior in rats exposed to chronic forced swim stress.

PubMed

Qi, Xiaoli; Lin, Wenjuan; Li, Junfa; Li, Huanhuan; Wang, Weiwen; Wang, Donglin; Sun, Meng

2008-08-01

Our previous research indicates that the extracellular signal-regulated kinase (ERK)-cyclic AMP-responsive-element-binding protein (CREB) signal system may be involved in the molecular mechanism of depression. The present study further investigated the effect of antidepressant fluoxetine on the ERK-CREB signal system and the depressive-like behaviors in rats. Fluoxetine was administrated to either naive rats or stressed rats for 21 days. The results showed that chronic forced swim stress induced depressive-like behaviors and decreased the levels of P-ERK2, P-CREB, ERK1/2 and CREB in hippocampus and prefrontal cortex. Fluoxetine alleviated the depressive-like behaviors and reversed the disruptions of the P-ERK2 and P-CREB in stressed rats. Fluoxetine also exerted mood-elevating effect and increased the levels of the P-ERK2 and P-CREB in naive rats. These results suggest that the ERK-CREB signal system may be the targets of the antidepressant action of fluoxetine and participate in the neuronal mechanism of depression.
Application of Fluorescence Spectrometry With Multivariate Calibration to the Enantiomeric Recognition of Fluoxetine in Pharmaceutical Preparations.

PubMed

Poláček, Roman; Májek, Pavel; Hroboňová, Katarína; Sádecká, Jana

2016-04-01

Fluoxetine is the most prescribed antidepressant chiral drug worldwide. Its enantiomers have a different duration of serotonin inhibition. A novel simple and rapid method for determination of the enantiomeric composition of fluoxetine in pharmaceutical pills is presented. Specifically, emission, excitation, and synchronous fluorescence techniques were employed to obtain the spectral data, which with multivariate calibration methods, namely, principal component regression (PCR) and partial least square (PLS), were investigated. The chiral recognition of fluoxetine enantiomers in the presence of β-cyclodextrin was based on diastereomeric complexes. The results of the multivariate calibration modeling indicated good prediction abilities. The obtained results for tablets were compared with those from chiral HPLC and no significant differences are shown by Fisher's (F) test and Student's t-test. The smallest residuals between reference or nominal values and predicted values were achieved by multivariate calibration of synchronous fluorescence spectral data. This conclusion is supported by calculated values of the figure of merit.
Cardiac transcriptional response to acute and chronic angiotensin II treatments.

PubMed

Larkin, Jennie E; Frank, Bryan C; Gaspard, Renee M; Duka, Irena; Gavras, Haralambos; Quackenbush, John

2004-07-08

Exposure of experimental animals to increased angiotensin II (ANG II) induces hypertension associated with cardiac hypertrophy, inflammation, and myocardial necrosis and fibrosis. Some of the most effective antihypertensive treatments are those that antagonize ANG II. We investigated cardiac gene expression in response to acute (24 h) and chronic (14 day) infusion of ANG II in mice; 24-h treatment induces hypertension, and 14-day treatment induces hypertension and extensive cardiac hypertrophy and necrosis. For genes differentially expressed in response to ANG II treatment, we tested for significant regulation of pathways, based on Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Microarray Pathway Profiler (GenMAPP) databases, as well as functional classes based on Gene Ontology (GO) terms. Both acute and chronic ANG II treatments resulted in decreased expression of mitochondrial metabolic genes, notably those for the electron transport chain and Krebs-TCA cycle; chronic ANG II treatment also resulted in decreased expression of genes involved in fatty acid metabolism. In contrast, genes involved in protein translation and ribosomal activity increased expression following both acute and chronic ANG II treatments. Some classes of genes showed differential response between acute and chronic ANG II treatments. Acute treatment increased expression of genes involved in oxidative stress and amino acid metabolism, whereas chronic treatments increased cytoskeletal and extracellular matrix genes, second messenger cascades responsive to ANG II, and amyloidosis genes. Although a functional linkage between Alzheimer disease, hypertension, and high cholesterol has been previously documented in studies of brain tissue, this is the first demonstration of induction of Alzheimer disease pathways by hypertension in heart tissue. This study provides the most comprehensive available survey of gene expression changes in response to acute and chronic ANG II treatment, verifying
Effect of SSRI antidepressants on ejaculation: a double-blind, randomized, placebo-controlled study with fluoxetine, fluvoxamine, paroxetine, and sertraline.

PubMed

Waldinger, M D; Hengeveld, M W; Zwinderman, A H; Olivier, B

1998-08-01

Depression is a common cause of sexual dysfunction, but also antidepressant medication is often associated with sexual side effects. This article includes two related studies. The first double-blind, placebo-controlled study was conducted in men with lifelong rapid ejaculation and aimed to assess putative differences between the major selective serotonin reuptake inhibitors (SSRIs) (fluoxetine, fluvoxamine, paroxetine, and sertraline) with regard to their ejaculation-delaying effect. Sixty men with an intravaginal ejaculation latency time (IELT) of 1 minute or less were randomly assigned to receive fluoxetine 20 mg/day, fluvoxamine 100 mg/day, paroxetine 20 mg/day, sertraline 50 mg/day, or placebo for 6 weeks. During the 1-month baseline and 6-week treatment periods, the men measured their IELT at home using a stopwatch. The trial was completed by 51 men. During the 6-week treatment period, the geometric mean IELT in the placebo group was constant at approximately 20 seconds. Analysis of variance revealed a between-groups difference in the evolution of IELT delay (p = 0.0004); in the paroxetine, fluoxetine, and sertraline groups there was a gradual increase to about 110 seconds, whereas in the fluvoxamine group, IELT was increased to only approximately 40 seconds. The paroxetine, fluoxetine, and sertraline groups differed significantly (p < 0.001, p < 0.001, p = 0.017, respectively) from placebo but the fluvoxamine group did not (p = 0.38). Compared with baseline, paroxetine exerted the strongest delay in ejaculation, followed by fluoxetine and sertraline. There was no clinically relevant delay in ejaculation with fluvoxamine. In men with lifelong rapid ejaculation, paroxetine delayed ejaculation most strongly, whereas fluvoxamine delayed ejaculation the least. The second double-blind, placebo-controlled study was carried out in men with lifelong rapid ejaculation (IELT < or = 1 minute) and in men with lifelong less-rapid ejaculation (IELT > 1 minute) to
[Acute lithium poisoning: epidemiology, clinical characteristics, and treatment].

PubMed

Burguera Vion, Víctor; Montes, José Manuel; Del Rey, José Manuel; Rivera-Gorrín, Maite; Rodao, José María; Tenorio, Maite; Saiz-Ruiz, Jerónimo; Liaño, Fernando

2017-02-01

Lithium continues to be the treatment of choice for bipolar disorder. Acute lithium poisoning is a potentially serious event. We present a retrospective observational significative study of episodes of acute lithium poisoning during a 52- month period. Poisoning was defined by a blood lithium concentration of 1.5 mEq/L or higher. We analyzed treatment and epidemiologic and clinical characteristics of 70 episodes were identified (incidence density among treated patients, 1.76 per 100 patient-years). The most frequent cause of lithium poisoning was a concurrent medical condition (46%). Most poisonings were mild (74.2%), but neurologic involvement was identified in 40.3%. Electrocardiographic abnormalities were found in 8 cases. Acute renal failure, found in 23 patients (37.1%), was mild in most cases, although 11 patients required hemodialysis. We concluded that acute lithium poisoning is an uncommon complication, but risk needs to be lowered. Patients should be warned to avoid dosage errors and to take special care during concurrent illnesses and while taking other medications.
Reactive oxygen species in the tumor niche triggers altered activation of macrophages and immunosuppression: Role of fluoxetine.

PubMed

Ghosh, Sayan; Mukherjee, Sudeshna; Choudhury, Sreetama; Gupta, Payal; Adhikary, Arghya; Baral, Rathindranath; Chattopadhyay, Sreya

2015-07-01

Macrophages are projected as one of the key players responsible for the progression of cancer. Classically activated (M1) macrophages are pro-inflammatory and have a central role in host defense, while alternatively activated (M2) macrophages are associated with immunosuppression. Macrophages residing at the site of neoplastic growth are alternately activated and are referred to as tumor-associated macrophages (TAMs). These "cooperate" with tumor tissue, promoting increased proliferation and immune escape. Selective serotonin reuptake inhibitors like fluoxetine have recently been reported to possess anti-inflammatory activity. We used fluoxetine to target tumor-associated inflammation and consequent alternate polarization of macrophages. We established that murine peritoneal macrophages progressed towards an altered activation state when exposed to cell-free tumor fluid, as evidenced by increased IL-6, IL-4 and IL-10 levels. These polarized macrophages showed significant pro-oxidant bias and increased p65 nuclear localization. It was further observed that these altered macrophages could induce oxidative insult and apoptosis in cultured mouse CD3(+) T cells. To validate these findings, we replicated key experiments in vivo, and observed that there was increased serum IL-6, IL-4 and IL-10 in tumor-bearing animals, with increased % CD206(+) cells within the tumor niche. TAMs showed increased nuclear localization of p65 with decreased Nrf2 expression in the nucleus. These results were associated with increase in apoptosis of CD3(+) T cells co-cultured with TAM-spent media. We could establish that fluoxetine treatment could specifically re-educate the macrophages both in vitro and in vivo by skewing their phenotype such that immune suppression mediated by tumor-dictated macrophages was successfully mitigated. Copyright © 2015 Elsevier Inc. All rights reserved.
Fluoxetine-clonazepam cotherapy for anxious depression: an exploratory, post-hoc analysis of a randomized, double blind study.

PubMed

Papakostas, George I; Clain, Alisabet; Ameral, Victoria E; Baer, Lee; Brintz, Carrie; Smith, Ward T; Londborg, Peter D; Glaudin, Vincent; Painter, John R; Fava, Maurizio

2010-01-01

Anxious depression, defined as major depressive disorder (MDD) accompanied by high levels of anxiety, seems to be both common and difficult to treat, with antidepressant monotherapy often yielding modest results. We sought to examine the relative benefits of antidepressant-anxiolytic cotherapy versus antidepressant monotherapy for patients with anxious depression versus without anxious depression. We conducted a post-hoc analysis of an existing dataset (N=80), from a 3-week, randomized, double-blind trial which demonstrated cotherapy with fluoxetine and clonazepam to result in superior efficacy than fluoxetine monotherapy in MDD. The present analysis involved examining whether anxious depression status served as a predictor and moderator of symptom improvement. Anxious depression status was not found to predict symptom improvement, or serve as a moderator of clinical improvement to cotherapy versus monotherapy. However, the advantage in remission rates in favor of cotherapy versus monotherapy was, numerically, much larger for patients with anxious depression (32.2%) than it was for patients without anxious MDD (9.7%). The respective number needed to treat statistic for these two differences in response rates were, approximately, one in three for patients with anxious depression versus one in 10 for patients without anxious depression. The efficacy of fluoxetine-clonazepam cotherapy compared with fluoxetine monotherapy was numerically but not statistically enhanced for patients with anxious depression than those without anxious depression.
[Sub-acute thyroiditis in a patient on immunosuppressive treatment].

PubMed

D'Amico, Giovanna; Di Crescenzo, Vincenzo; Caleo, Alessia; Garzi, Alfredo; Vitale, Mario

2013-01-01

Sub-acute thyroiditis or De Quervain's thyroiditis is a viral, inflammatory disease which causes the serum release of thyroidal hormones and hyperthyroidism. The pathogenesis of thyroid follicle damage is unclear because the exclusive viral action or a concomitant autoimmune component, determined by the lymphoid infiltrate remain to be assessed. We describe the case of a patient under immunosuppressive treatment, who developed sub-acute thyroiditis with hormone release and hyperthyroidism. The patient, while was under immunosuppressive treatment for kidney transplant, exhibited a clinical picture and hormonal profile of hyperthyroidism. Thyroid scintiscan exhibited an extremely low uptake. Fine-needle cytologic diagnosis was granulomatous sub-acute thyroiditis (De Quervain's thyroiditis). This case suggests the primary or even exclusive role of the viral infection in hormone release and hyperthyroidism in sub-acute thyroiditis, excluding an autoimmune component.
Modelling the cost effectiveness of antidepressant treatment in primary care.

PubMed

Revicki, D A; Brown, R E; Palmer, W; Bakish, D; Rosser, W W; Anton, S F; Feeny, D

1995-12-01

The aim of this study was to estimate the cost effectiveness of nefazodone compared with imipramine or fluoxetine in treating women with major depressive disorder. Clinical decision analysis and a Markov state-transition model were used to estimate the lifetime health outcomes and medical costs of 3 antidepressant treatments. The model, which represents ideal primary care practice, compares treatment with nefazodone to treatment with either imipramine or fluoxetine. The economic analysis was based on the healthcare system of the Canadian province of Ontario, and considered only direct medical costs. Health outcomes were expressed as quality-adjusted life years (QALYs) and costs were in 1993 Canadian dollars ($Can; $Can1 = $US0.75, September 1995). Incremental cost-utility ratios were calculated comparing the relative lifetime discounted medical costs and QALYs associated with nefazodone with those of imipramine or fluoxetine. Data for constructing the model and estimating necessary parameters were derived from the medical literature, clinical trial data, and physician judgement. Data included information on: Ontario primary care physicians' clinical management of major depression; medical resource use and costs; probabilities of recurrence of depression; suicide rates; compliance rates; and health utilities. Estimates of utilities for depression-related hypothetical health states were obtained from patients with major depression (n = 70). Medical costs and QALYs were discounted to present value using a 5% rate. Sensitivity analyses tested the assumptions of the model by varying the discount rate, depression recurrence rates, compliance rates, and the duration of the model. The base case analysis found that nefazodone treatment costs $Can1447 less per patient than imipramine treatment (discounted lifetime medical costs were $Can50,664 vs $Can52,111) and increases the number of QALYs by 0.72 (13.90 vs 13.18). Nefazodone treatment costs $Can14 less than fluoxetine
Fluoxetine for Maintenance of Remission and to Improve Quality of Life in Patients with Crohn's Disease: a Pilot Randomized Placebo-Controlled Trial.

PubMed

Mikocka-Walus, Antonina; Hughes, Patrick A; Bampton, Peter; Gordon, Andrea; Campaniello, Melissa A; Mavrangelos, Chris; Stewart, Benjamin J; Esterman, Adrian; Andrews, Jane M

2017-04-01

Previous studies have shown that antidepressants reduce inflammation in animal models of colitis. The present trial aimed to examine whether fluoxetine added to standard therapy for Crohn's disease [CD] maintained remission, improved quality of life [QoL] and/or mental health in people with CD as compared to placebo. A parallel randomized double-blind placebo controlled trial was conducted. Participants with clinically established CD, with quiescent or only mild disease, were randomly assigned to receive either fluoxetine 20 mg daily or placebo, and followed for 12 months. Participants provided blood and stool samples and completed mental health and QoL questionnaires. Immune functions were assessed by stimulated cytokine secretion [CD3/CD28 stimulation] and flow cytometry for cell type. Linear mixed-effects models were used to compare groups. Of the 26 participants, 14 were randomized to receive fluoxetine and 12 to placebo. Overall, 14 [54%] participants were male. The mean age was 37.4 [SD=13.2] years. Fluoxetine had no effect on inflammatory bowel disease activity measured using either the Crohn's Disease Activity Index [F(3, 27.5)=0.064, p=0.978] or faecal calprotectin [F(3, 32.5)=1.08, p=0.371], but did have modest effects on immune function. There was no effect of fluoxetine on physical, psychological, social or environmental QoL, anxiety or depressive symptoms as compared to placebo [all p>0.05]. In this small pilot clinical trial, fluoxetine was not superior to placebo in maintaining remission or improving QoL. [ID: ACTRN12612001067864.]. © European Crohn’s and Colitis Organistion (ECCO) 2016.
On-line solid phase extraction coupled to capillary LC-ESI-MS for determination of fluoxetine in human blood plasma.

PubMed

Saber, Amr L

2009-04-15

An instrumental setup including on-line solid phased extraction coupled to capillary liquid chromatography-electrospray ionization-mass spectrometry (SPE-capLC-ESI-MS) has been constructed to improve the sensitivity for quantification of fluoxetine hydrochloride in human plasma. Prior to injection, 0.5 mL of plasma spiked with metronidazole (internal standard) was mixed with ammonium formate buffer for effective chloroform liquid-liquid extraction. The method was validated in the range 5-60 ng mL(-1) fluoxetine, yielding a correlation coefficient of 0.999 (r(2)). The within-assay and between-assay precisions were between (8.5 and 11%) and (6.6 and 7.5%), respectively. The method was used to determine the amount of fluoxetine in a healthy male 14 h after an intake of one capsule of the antidepressant and anorectic Flutin, which contains 20mg fluoxetine per each capsule. Fluoxetine was detected, and the concentration was calculated to 9.0 ng mL(-1) plasma. In the preliminary experiments, conventional LC-UV instrumentation was employed. However, it was found that employing a capillary column with an inner diameter of (0.3mm I.D. x 50 mm, Zorbax C(18)) increased the sensitivity by a factor of approximately 100, when injecting the same mass of analyte. Incorporating an easily automated C(18) reversed phase column switching system with SPE (1.0mm I.D. x 5.0mm, 5 microm) made it possible to inject up to 100 microL of solution, and the total analysis time was 5.5 min.

Neuroendocrine disruption in the shore crab Carcinus maenas: Effects of serotonin and fluoxetine on chh- and mih-gene expression, glycaemia and ecdysteroid levels.

PubMed

Robert, Alexandrine; Monsinjon, Tiphaine; Delbecque, Jean-Paul; Olivier, Stéphanie; Poret, Agnès; Foll, Frank Le; Durand, Fabrice; Knigge, Thomas

2016-06-01

Serotonin, a highly conserved neurotransmitter, controls many biological functions in vertebrates, but also in invertebrates. Selective serotonin reuptake inhibitors (SSRIs), such as fluoxetine, are commonly used in human medication to ease depression by affecting serotonin levels. Their residues and metabolites can be detected in the aquatic environment and its biota. They may also alter serotonin levels in aquatic invertebrates, thereby perturbing physiological functions. To investigate whether such perturbations can indeed be expected, shore crabs (Carcinus maenas) were injected either with serotonin, fluoxetine or a combination of both. Dose-dependent effects of fluoxetine ranging from 250 to 750nM were investigated. Gene expression of crustacean hyperglycemic hormone (chh) as well as moult inhibiting hormone (mih) was assessed by RT-qPCR at 2h and 12h after injection. Glucose and ecdysteroid levels in the haemolymph were monitored in regular intervals until 12h. Serotonin led to a rapid increase of chh and mih expression. On the contrary, fluoxetine only affected chh and mih expression after several hours, but kept expression levels significantly elevated. Correspondingly, serotonin rapidly increased glycaemia, which returned to normal or below normal levels after 12h. Fluoxetine, however, resulted in a persistent low-level increase of glycaemia, notably during the period when negative feedback regulation reduced glycaemia in the serotonin treated animals. Ecdysteroid levels were significantly decreased by serotonin and fluoxetine, with the latter showing less pronounced and less rapid, but longer lasting effects. Impacts of fluoxetine on glycaemia and ecdysteroids were mostly observed at higher doses (500 and 750nM) and affected principally the response dynamics, but not the amplitude of glycaemia and ecdysteroid-levels. These results suggest that psychoactive drugs are able to disrupt neuroendocrine control in decapod crustaceans, as they interfere with the
Optimization of alcohol-assisted dispersive liquid-liquid microextraction by experimental design for the rapid determination of fluoxetine in biological samples.

PubMed

Hamedi, Raheleh; Hadjmohammadi, Mohammad Reza

2016-12-01

A sensitive and rapid method based on alcohol-assisted dispersive liquid-liquid microextraction followed by high-performance liquid chromatography for the determination of fluoxetine in human plasma and urine samples was developed. The effects of six parameters on the extraction recovery were investigated and optimized utilizing Plackett-Burman design and Box-Benken design, respectively. According to the Plackett-Burman design results, the volume of disperser solvent, extraction time, and stirring speed had no effect on the recovery of fluoxetine. The optimized conditions included a mixture of 172 μL of 1-octanol as extraction solvent and 400 μL of methanol as disperser solvent, pH of 11.3 and 0% w/v of salt in the sample solution. Replicating the experiment in optimized condition for five times, gave the average extraction recoveries equal to 90.15%. The detection limit of fluoxetine in human plasma was obtained 3 ng/mL, and the linearity was in the range of 10-1200 ng/mL. The corresponding values for human urine were 4.2 ng/mL with the linearity range from 10 to 2000 ng/mL. Relative standard deviations for intra and inter day extraction of fluoxetine were less than 7% in five measurements. The developed method was successfully applied for the determination of fluoxetine in human plasma and urine samples. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
Dissociations between interval timing and intertemporal choice following administration of fluoxetine, cocaine, or methamphetamine

PubMed Central

Heilbronner, Sarah R.; Meck, Warren. H.

2014-01-01

The goal of our study was to characterize the relationship between intertemporal choice and interval timing, including determining how drugs that modulate brain serotonin and dopamine levels influence these two processes. In Experiment 1, rats were tested on a standard 40-s peak-interval procedure following administration of fluoxetine (3, 5, or 8 mg/kg) or vehicle to assess basic effects on interval timing. In Experiment 2, rats were tested in a novel behavioral paradigm intended to simultaneously examine interval timing and impulsivity. Rats performed a variant of the bi-peak procedure using 10-s and 40-s target durations with an additional “defection” lever that provided the possibility of a small, immediate reward. Timing functions remained relatively intact, and ‘patience’ across subjects correlated with peak times, indicating a negative relationship between ‘patience’ and clock speed. We next examined the effects of fluoxetine (5 mg/kg), cocaine (15 mg/kg), or methamphetamine (1 mg/kg) on task performance. Fluoxetine reduced impulsivity as measured by defection time without corresponding changes in clock speed. In contrast, cocaine and methamphetamine both increased impulsivity and clock speed. Thus, variations in timing may mediate intertemporal choice via dopaminergic inputs. However, a separate, serotonergic system can affect intertemporal choice without affecting interval timing directly. PMID:24135569
Cost-effectiveness analysis of pharmacologic treatment of fibromyalgia in Mexico.

PubMed

Arreola Ornelas, Héctor; Rosado Buzzo, Alfonso; García, Lourdes; Dorantes Aguilar, Javier; Contreras Hernández, Iris; Mould Quevedo, Joaquín F

2012-01-01

To identify, from the Mexican Public Health System perspective, which would be the most cost-effective treatment for patients with Fibromyalgia (FM). A Markov model including three health states, divided by pain intensity (absence or presence of mild, moderate or severe pain) and considering three-month cycles; costs and effectiveness were estimated for amitriptyline (50mg/day), fluoxetine (80 mg/day), duloxetine (120 mg/day), gabapentin (900 mg/day), pregabalin (450 mg/day), tramadol/acetaminophen (150 mg/1300 mg/día) and amitriptyline/fluoxetine (50mg/80 mg/día) for the treatment of FM. The clinical outcome considered was the annual rate of pain control. Probabilities assigned to the model were collected from published literature. Direct medical costs for FM treatment were retrieved from the 2006 data of the Mexican Institute of Social Security (IMSS) databases and were expressed in 2010 Mexican Pesos. Probabilistic Sensitivity Analyses were conducted. The best pain control rate was obtained with pregabalin (44.8%), followed by gabapentin (38.1%) and duloxetine (34.2%). The lowest treatment costs was for amitriptyline ($ 9047.01), followed by fluoxetine ($ 10,183.89) and amitriptyline/fluoxetine ($ 10,866.01). By comparing pregabalin vs amitriptyline, additional annual cost per patient for pain control would be around $ 50.000 and $ 75.000 and would result cost-effective in 70% and 80% of all cases. Among all treatment options for FM, pregabalin achieved the highest pain control and was cost-effective in 80% of patients of the Mexican Public Health System. Copyright © 2011 Elsevier España, S.L. All rights reserved.
Adding Group Psychotherapy to Medication Treatment in Dysthymia

PubMed Central

Hellerstein, David J.; Little, Suzanne A. S.; Samstag, Lisa Wallner; Batchelder, Sarai; Muran, J. Christopher; Fedak, Michael; Kreditor, David; Rosenthal, Richard N.; Winston, Arnold

2001-01-01

Patients with dysthymia have been shown to respond to treatment with antidepressant medications, and to some degree to psychotherapy. Even patients successfully treated with medication often have residual symptoms and impaired psychosocial functioning. The authors describe a prospective randomized 36-week study of dysthymic patients, comparing continued treatment with antidepressant medication (fluoxetine) alone and medication with the addition of group therapy treatment. After an 8-week trial of fluoxetine, medication-responsive subjects were randomly assigned to receive either continued medication only or medication plus 16 sessions of manualized group psychotherapy. Results provide preliminary evidence that group therapy may provide additional benefit to medication-responding dysthymic patients, particularly in interpersonal and psychosocial functioning. PMID:11264333
Re-evaluating the treatment of acute optic neuritis

PubMed Central

Bennett, Jeffrey L; Nickerson, Molly; Costello, Fiona; Sergott, Robert C; Calkwood, Jonathan C; Galetta, Steven L; Balcer, Laura J; Markowitz, Clyde E; Vartanian, Timothy; Morrow, Mark; Moster, Mark L; Taylor, Andrew W; Pace, Thaddeus W W; Frohman, Teresa; Frohman, Elliot M

2015-01-01

Clinical case reports and prospective trials have demonstrated a reproducible benefit of hypothalamic-pituitary-adrenal (HPA) axis modulation on the rate of recovery from acute inflammatory central nervous system (CNS) demyelination. As a result, corticosteroid preparations and adrenocorticotrophic hormones are the current mainstays of therapy for the treatment of acute optic neuritis (AON) and acute demyelination in multiple sclerosis. Despite facilitating the pace of recovery, HPA axis modulation and corticosteroids have failed to demonstrate long-term benefit on functional recovery. After AON, patients frequently report visual problems, motion perception difficulties and abnormal depth perception despite ‘normal’ (20/20) vision. In light of this disparity, the efficacy of these and other therapies for acute demyelination require re-evaluation using modern, high-precision paraclinical tools capable of monitoring tissue injury. In no arena is this more amenable than AON, where a new array of tools in retinal imaging and electrophysiology has advanced our ability to measure the anatomic and functional consequences of optic nerve injury. As a result, AON provides a unique clinical model for evaluating the treatment response of the derivative elements of acute inflammatory CNS injury: demyelination, axonal injury and neuronal degeneration. In this article, we examine current thinking on the mechanisms of immune injury in AON, discuss novel technologies for the assessment of optic nerve structure and function, and assess current and future treatment modalities. The primary aim is to develop a framework for rigorously evaluating interventions in AON and to assess their ability to preserve tissue architecture, re-establish normal physiology and restore optimal neurological function. PMID:25355373
Assessing biological effects of fluoxetine in developing zebrafish embryos using gas chromatography-mass spectrometry based metabolomics.

PubMed

Mishra, Priti; Gong, Zhiyuan; Kelly, Barry C

2017-12-01

Continuous low-dose exposure of pharmaceutically active compounds (PhACs) in aquatic ecosystems is a concern worldwide. In this study, we utilized a gas chromatography mass spectrometry (GC-MS) based metabolomics approach to assess endogenous metabolite changes in developing zebrafish embryos exposed to different concentrations of the widely used antidepressant, fluoxetine. Embryos were exposed from 2 h post fertilization (hpf) until 96 hpf. Using the Fiehn GC-MS library, a total of 31 metabolites were positively identified in embryos. Statistical analyses revealed significant dysregulation of 11 metabolites in fluoxetine exposed embryos. Metabolite classes that were significantly altered included, amino acids, monosaccharides, glycerophosphates, fatty acids, carboxylic acid derivatives and sugars. Concentrations of amino acids, maltose, d-malic acid, 3-phosphoglycerate and d-glucose were significantly reduced in exposed embryos. Conversely, concentrations of citric acid were in some cases significantly elevated in exposed embryos. Metabolic pathway analysis revealed perturbation of five main pathways, including (i) alanine, aspartate and glutamate metabolism, (ii) phenylalanine, tyrosine and tryptophan biosynthesis, (iii) phenylalanine metabolism. (iv) tyrosine metabolism and (v) starch and sucrose metabolism. The results indicate fluoxetine exposure causes perturbation of energy and amino acid metabolism, which may adversely impact embryogenesis due to depletion of energy reserves during this period. Also, the observed alterations in aspartic acid, phenylalanine and tyrosine in fluoxetine exposed embryos suggests potential disruption of normal neurobehavioral and liver function. The results further demonstrate that GC-MS based metabolomics is an effective approach for assessing toxicodynamics and threshold effect levels of environmental pollutants in aquatic organisms. Copyright © 2017 Elsevier Ltd. All rights reserved.
Developmental fluoxetine and prenatal stress effects on serotonin, dopamine, and synaptophysin density in the PFC and hippocampus of offspring at weaning.

PubMed

Gemmel, Mary; Rayen, Ine; Lotus, Tiffany; van Donkelaar, Eva; Steinbusch, Harry W; De Lacalle, Sonsoles; Kokras, Nikolaos; Dalla, Christina; Pawluski, Jodi L

2016-04-01

Selective serotonin reuptake inhibitor medication exposure during the perinatal period can have a long term impact in adult offspring on neuroplasticity and the serotonergic system, but the impact of these medications during early development is poorly understood. The aim of this study was to determine the effects of developmental exposure to the SSRI, fluoxetine, on the serotonergic system, dopaminergic system, and synaptophysin density in the prefrontal cortex and hippocampus, as well as number of immature neurons in the dentate gyrus, in juvenile rat offspring at weaning. To model aspects of maternal depression, prenatal restraint stress was used. Sprague-Dawley rat offspring were exposed to either prenatal stress and/or fluoxetine. Main findings show that developmental fluoxetine exposure to prenatally stressed offspring decreased 5-HT and 5-HIAA levels and altered the dopaminergic system in the hippocampus. Prenatal stress, regardless of fluoxetine, increased synaptophysin density in the PFC. This work indicates that early exposure to maternal stress and SSRI medication can alter brain monoamine levels and synaptophysin density in offspring at weaning. © 2015 Wiley Periodicals, Inc.
The Synergistic Effect of Raloxifene, Fluoxetine, and Bromocriptine Protects Against Pilocarpine-Induced Status Epilepticus and Temporal Lobe Epilepsy.

PubMed

Pottoo, Faheem Hyder; Tabassum, Nahida; Javed, Md Noushad; Nigar, Shah; Rasheed, Rouqia; Khan, Ayash; Barkat, Md Abul; Alam, Md Sabir; Maqbool, Amir; Ansari, Mohammad Azam; Barreto, George E; Ashraf, Ghulam Md

2018-06-07

The present antiepileptic drugs pose several problems in the management of seizures owing to their meager neuroprotective potential, adverse effects on bone, detrimental effects on cognitive function, chronic toxicity, drug interactions, side effects including aggression, agitation, and irritability and sometimes exacerbation of seizures. We followed up progressive preclinical investigation in mice against pilocarpine (PILO)-induced status epilepticus (SE) and temporal lobe epilepsy (TLE). To determine the response of raloxifene (RF) (4 and 8 mg/kg), fluoxetine (FT) (14 and 22 mg/kg), bromocriptine (BC) (6 and 10 mg/kg), and their low-dose combinations, oral treatment was scheduled for 28 days followed by PILO (300 mg/kg, i.p). The response was stalked for intensive behavioral monitoring of convulsions, hippocampal neuropeptide Y (NPY), and oxidative stress discernment along with histomorphological studies. The resultant data confirmed the therapeutic potential of triple drug combination of raloxifene (4 mg/kg) with fluoxetine (14 mg/kg) and bromocriptine (6 mg/kg) compared to monotherapy with raloxifene (4 mg/kg), and bromocriptine (6 mg/kg) as otherwise monotherapy with fluoxetine (14 mg/kg) was ineffective to suppress convulsions; an effect better than sodium valproate (300 mg/kg), a standard AED, was validated. Most profoundly, PILO-induced compensatory increases in hippocampal NPY levels (20.01%), which was escalated (100%) with the triple drug combination. The same pattern of results was superseded for oxidative stress indices and neuronal damage. The results for the first time demonstrate the propitious role of triple drug combination in the management of SE and TLE. Therapeutically, this enhancing profile of drugs fosters a safer and more effective drug-combination regimen. Graphical abstract ᅟ.
Subacute Fluoxetine Reduces Signs of Hippocampal Damage Induced by a Single Convulsant Dose of 4-Aminopyridine in Rats.

PubMed

Shiha, Ahmed A; de la Rosa, Rubén Fernández; Delgado, Mercedes; Pozo, Miguel A; García-García, Luis

2017-01-01

Epilepsy is a central disorder associated with neuronal damage and brain hypometabolism. It has been reported that antidepressant drugs show anticonvulsant and neuroprotective effects in different animal models of seizures and epilepsy. The purpose of this study was to investigate the eventual short-term brain impairment induced by a single low convulsant dose of the potassium channel blocker 4-aminopyridine (4-AP) and the eventual neuroprotective effects exerted by fluoxetine, a prototypical selective serotonin (5-hydroxytryptamine; 5-HT) reuptake inhibitor (SSRI). In vivo 2-deoxy-2-[18F]fluoro-D-glucose ([18F]FDG) positron emission tomography (PET) and several histological assessments were carried out in adult male rats after i.p. administration of 3 mg/kg 4-AP for evaluating eventual brain metabolism impairment and signs of hippocampal damage. We also evaluated the effects of a short-term fluoxetine treatment (10 mg/kg, i.p. for 7 days) in this seizure model. [18F]FDG PET analysis revealed no changes in the regional brain metabolism on day 3 after 4-AP injection. The histological assessments revealed signs of damage in the hippocampus, a brain area usually affected by seizures. Thus, reactive gliosis and a significant increase in the expression of caspase-9 were found in the aforementioned brain area. By contrast, we observed no signs of neurodegeneration or neuronal death. Regarding the effects of fluoxetine, this SSRI showed beneficial neurologic effects, since it significantly increased the seizure latency time and reduced the abovementioned 4-AP-induced hippocampal damage markers. Overall, our results point to SSRIs and eventually endogenous 5-HT as neuroprotective agents against convulsant-induced hippocampal damage. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.
Effects of swim stress and fluoxetine on 5-HT1A receptor gene expression and monoamine metabolism in the rat brain regions.

PubMed

Shishkina, G T; Kalinina, T S; Dygalo, N N

2012-07-01

Changes in gene expression of the brain serotonin (5-HT) 1A receptors may be important for the development and ameliorating depression, however identification of specific stimuli that activate or reduce the receptor transcriptional activity is far from complete. In the present study, the forced swim test (FST) exposure, the first stress session of which is already sufficient to induce behavioral despair in rats, significantly increased 5-HT1A receptor mRNA levels in the brainstem, frontal cortex, and hippocampus at 24 h. In the brainstem and frontal cortex, the elevation in the receptor gene expression after the second forced swim session was not affected following chronic administration of fluoxetine, while in the cortex, both control and FST values were significantly reduced in fluoxetine-treated rats. In contrast to untreated rats, no increase in hippocampal 5-HT1A receptor mRNA was observed in response to FST in rats chronically treated with fluoxetine. Metabolism of 5-HT (5-HIAA/5-HT) in the brainstem was significantly decreased by fluoxetine and further reduced by swim stress, showing a certain degree of independence of these changes on 5-HT1A receptor gene expression that was increased in this brain region only after the FST, but not after fluoxetine. FST exposure also decreased the brainstem dopamine metabolism, which was unexpectedly positively correlated with 5-HT1A receptor mRNA levels in the frontal cortex. Together, these data suggest that the effects of the forced swim stress as well as fluoxetine involve brain region-dependent alterations in 5-HT1A receptor gene transcription, some of which may be interrelated with concomitant changes in catecholamine metabolism.
Acute agmatine administration, similar to ketamine, reverses depressive-like behavior induced by chronic unpredictable stress in mice.

PubMed

Neis, Vivian B; Bettio, Luis E B; Moretti, Morgana; Rosa, Priscila B; Ribeiro, Camille M; Freitas, Andiara E; Gonçalves, Filipe M; Leal, Rodrigo B; Rodrigues, Ana Lúcia S

Agmatine is an endogenous neuromodulator that has been shown to have antidepressant-like properties. We have previously demonstrated that it can induce a rapid increase in BDNF levels after acute administration, suggesting that agmatine may be a fast-acting antidepressant. To investigate this hypothesis, the present study evaluated the effects of a single administration of agmatine in mice subjected to chronic unpredictable stress (CUS), a model of depression responsive only to chronic treatment with conventional antidepressants. The ability of agmatine to reverse CUS-induced behavioral and biochemical alterations was evaluated and compared with those elicited by the fast-acting antidepressant (ketamine) and the conventional antidepressant (fluoxetine). After exposed to CUS for 14days, mice received a single oral dose of agmatine (0.1mg/kg), ketamine (1mg/kg) or fluoxetine (10mg/kg), and were submitted to behavioral evaluation after 24h. The exposure to CUS caused an increased immobility time in the tail suspension test (TST) but did not change anhedonic-related parameters in the splash test. Our findings provided evidence that, similarly to ketamine, agmatine is able to reverse CUS-induced depressive-like behavior in the TST. Western blot analyses of prefrontal cortex (PFC) demonstrated that mice exposed to CUS and/or treated with agmatine, fluoxetine or ketamine did not present alterations in the immunocontent of synaptic proteins [i.e. GluA1, postsynaptic density protein 95 (PSD-95) and synapsin]. Altogether, our findings indicate that a single administration of agmatine is able to reverse behavioral alterations induced by CUS in the TST, suggesting that this compound may have fast-acting antidepressant-like properties. However, there was no alteration in the levels of synaptic proteins in the PFC, a result that need to be further investigated in other time points. Copyright Â© 2016 Elsevier Inc. All rights reserved.
Cost considerations of acute migraine treatment.

PubMed

Adelman, James U; Adelman, Leon C; Freeman, Marshall C; Von Seggern, Randal L; Drake, Jaclyn

2004-03-01

To provide medication price data and cost-reducing strategies for the acute treatment of migraine. Retail prices for common acute care medications were found at http://www.drugstore.com. Cost-reduction tactics were obtained from literature searches and clinical experience. Several strategies can reduce cost without sacrificing treatment outcome. In mild to moderate migraine, low-priced nonsteroidal anti-inflammatory drugs can be used as first-line medications due to their proven efficacy and favorable tolerability. For patients with more severe migraine, implementing a stratified care approach-using migraine-specific medications early in acute treatment-is cost-effective for most patients. Stratified care not only improves outcome and decreases disability, but also reduces cost. Pill splitting and early administration of triptans within an attack enhance their value. Supplying rescue medications, such as opioids, sedatives, and phenothiazines, can prevent emergency department visits. Minimizing multiple dosing of triptans and reducing utilization of expensive health care resources are key factors in reducing the cost of effective migraine treatment. An important affordability factor for patients with co-payments is the number of triptan pills per package. Sumatriptan, naratriptan, and frovatriptan each contain 9 tablets per package, while most other triptan packages contain 6. Current triptan retail prices (per unit) include: Amerge 1 and 2.5 mg, 17.78 dollars; Axert 6.25 and 12.5 mg, 16.31 dollars; Frova 2.5 mg, 13.89 dollars; Imitrex 50 mg, 14.96 dollars; Imitrex 100 mg, 14.41 dollars; Imitrex Nasal Spray 20 mg, 21.61 dollars; Imitrex SQ 6 mg, 50.26 dollars; Maxalt 5 and 10 mg, 15 dollars; Maxalt-MLT 5 and 10 mg, 15 dollars; Relpax 40 mg, 13.58 dollars; Zomig 2.5 mg, 13.67 dollars; Zomig 5 mg, 15.89 dollars; Zomig-ZMT 2.5 mg, 13.67 dollars; and Zomig-ZMT 5 mg, 15.89 dollars. Practitioners can optimize the use of health care dollars without compromising quality of
A systematic review on the treatment of acute ankle sprain: brace versus other functional treatment types.

PubMed

Kemler, Ellen; van de Port, Ingrid; Backx, Frank; van Dijk, C Niek

2011-03-01

Ankle injuries, especially ankle sprains, are a common problem in sports and medical care. Ankle sprains result in pain and absenteeism from work and/or sports participation, and can lead to physical restrictions such as ankle instability. Nowadays, treatment of ankle injury basically consists of taping the ankle. The purpose of this review is to evaluate the effectiveness of ankle braces as a treatment for acute ankle sprains compared with other types of functional treatments such as ankle tape and elastic bandages. A computerized literature search was conducted using PubMed, EMBASE, CINAHL and the Cochrane Clinical Trial Register. This review includes randomized controlled trials in English, German and Dutch, published between 1990 and April 2009 that compared ankle braces as a treatment for lateral ankle sprains with other functional treatments. The inclusion criteria for this systematic review were (i) individuals (sports participants as well as non-sports participants) with an acute injury of the ankle (acute ankle sprains); (ii) use of an ankle brace as primary treatment for acute ankle sprains; (iii) control interventions including any other type of functional treatment (e.g. Tubigrip™, elastic wrap or ankle tape); and (iv) one of the following reported outcome measures: re-injuries, symptoms (pain, swelling, instability), functional outcomes and/or time to resumption of sports, daily activities and/or work. Eight studies met all inclusion criteria. Differences in outcome measures, intervention types and patient characteristics precluded pooling of the results, so best evidence syntheses were conducted. A few individual studies reported positive outcomes after treatment with an ankle brace compared with other functional methods, but our best evidence syntheses only demonstrated a better treatment result in terms of functional outcome. Other studies have suggested that ankle brace treatment is a more cost-effective method, so the use of braces after acute
The burden and management of cytochrome P450 2D6 (CYP2D6)-mediated drug-drug interaction (DDI): co-medication of metoprolol and paroxetine or fluoxetine in the elderly.

PubMed

Bahar, Muh Akbar; Hak, Eelko; Bos, Jens H J; Borgsteede, Sander D; Wilffert, Bob

2017-07-01

Metoprolol and paroxetine/fluoxetine are inevitably co-prescribed because cardiovascular disorders and depression often coexist in the elderly. This leads to CYP2D6-mediated drug-drug interactions (DDI). Because systematic evaluations are lacking, we assessed the burden of metoprolol-paroxetine/fluoxetine interaction in the elderly and how these interactions are managed in Dutch community pharmacies. Dispensing data were collected from the University of Groningen pharmacy database (IADB.nl, 1999-2014) for elderly patients (≥60 years) starting beta-blockers and/or antidepressants. Based on the two main DDI alert systems (G-Standard and Pharmabase), incidences were divided between signalled (metoprolol-fluoxetine/paroxetine) and not-signalled (metoprolol-alternative antidepressants and alternative beta-blockers-paroxetine/fluoxetine) combinations. Incident users were defined as patients starting at least one signalled or a non-signalled combination. G-Standard signalled throughout the study period, whereas Pharmabase stopped after 2005. A total of 1763 patients had 2039 metoprolol-paroxetine/fluoxetine co-prescriptions, despite DDI alert systems, and about 57.3% were signalled. The number of metoprolol-alternative antidepressant combinations (incidences = 3150) was higher than alternative beta-blocker-paroxetine/fluoxetine combinations (incidences = 1872). Metoprolol users are more likely to be co-medicated with an alternative antidepressant (incidences = 2320) than paroxetine/fluoxetine users (incidences = 1232) are. The number of paroxetine/fluoxetine users co-prescribed with alternative beta-blockers was comparable to those co-medicated with metoprolol (about 50%). Less than 5% of patients received a substitute therapy after using metoprolol-paroxetine/fluoxetine. Most of the metoprolol users (90%) received a low dose (mean DDD = 0.47) regardless whether they were prescribed paroxetine/fluoxetine. Despite the signalling software, metoprolol-paroxetine/fluoxetine
The antidepressant fluoxetine normalizes the nuclear glucocorticoid receptor evoked by psychosocial stress

NASA Astrophysics Data System (ADS)

Mitić, M.; Simić, I.; Djordjević, J.; Radojčić, M. B.; Adžić, M.

2011-12-01

Dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis has been implicated in the pathophysiology of depression and stress disorders. Glucocorticoids, key regulators of the stress response, exert diverse effects on cellular processes in the hippocampus. Beside non-genomic pathways, glucocorticoid effects are mediated through activation of the glucocorticoid receptor (GR), a ligand activated transcriptional factor that belongs to the nuclear hormone receptor superfamily. We analysed the GR protein levels both in the cytoplasmic and nuclear compartments of the hippocampus of Wistar rats exposed to chronic psychosocial isolation stress upon chronic fluoxetine (FLU) treatment. Under chronic stress, corticosterone levels (CORT) were decreased compared to the control, and treatment with FLU did not change its level in the stressed rats. At the molecular level, FLU normalized the level of nuclear GR protein in the hippocampus of the stressed rats. Discrepancy between normalization of nuclear GR in the hippocampus and lack of normalization of HPA axis activity judged by CORT, suggests that other brain structures such as the amygdale and prefrontal cortex that also regulate HPA axis activity, seem not to be normalized by the FLU treatment used in our study.
Perinatal fluoxetine effects on social play, the HPA system, and hippocampal plasticity in pre-adolescent male and female rats: Interactions with pre-gestational maternal stress.

PubMed

Gemmel, Mary; Hazlett, Mariah; Bögi, Eszter; De Lacalle, Sonsoles; Hill, Lesley A; Kokras, Nikolaos; Hammond, Geoffrey L; Dalla, Christina; Charlier, Thierry D; Pawluski, Jodi L

2017-10-01

Selective serotonin reuptake inhibitor medications (SSRIs) are the first lines of treatment for maternal affective disorders, and are prescribed to up to 10% of pregnant women. Concern has been raised about how perinatal exposure to these medications affect offspring neurobehavioral outcomes, particularly those related to social interactions, as recent research has reported conflicting results related to autism spectrum disorder (ASD) risk in children prenatally exposed to SSRIs. Therefore, the aim of this work was to investigate the effects of perinatal exposure to the SSRI fluoxetine on social play behaviors and the hypothalamic pituitary adrenal system, using a model of pre-gestational maternal stress. We also investigated synaptic proteins in the CA2, CA3, and dentate gyrus of the hippocampus, as well as number of immature neurons in the granule cell layer, as both measures of plasticity in the hippocampus have been linked to social behaviors. In pre-adolescent male and female Sprague-Dawley rat offspring, main findings show that perinatal fluoxetine prevents the negative effect of maternal stress on sibling play behavior. However, perinatal fluoxetine increased social aggressive play with a novel conspecific in both sexes and decreased time grooming a novel conspecific in males only. Perinatal fluoxetine also increased serum corticosteroid binding globulin levels, 5-HT levels in the hippocampus, and pre-synaptic density assessed via synaptophysin in the dentate gyrus. Social interaction was significantly correlated with changes in plasticity in the CA2 region of the hippocampus. Pre-gestational maternal stress exposure resulted in significantly decreased rates of hippocampal neurogenesis and synaptophysin density in the dentate gyrus of pre-adolescent males, but not females. Together, these results further characterize the role of perinatal SSRIs, maternal stress prior to conception, and sex/gender on developing social behaviors and related plasticity in the
Topical nitroglycerin ointment for treatment of acute hypertension in hospitalized inpatients.

PubMed

Brower, Kathryn A; Garcia, Nelson A Telles; Smith, Hayden L; Wall, Geoffrey C

2015-05-01

Hypertension in the hospital setting is common; however, guidelines provide limited guidance specific to the inpatient setting. Acute antihypertensive treatment options can be limited in this setting by monitoring requirements of intravenous medications and patients' inability to take oral medications. A possible treatment choice used to treat acute hypertension is nitroglycerin ointment. Nitroglycerin is not approved by the Food and Drug Administration for this condition, and limited evidence exists to support this indication. To evaluate the statistical and clinical effectiveness of nitroglycerin ointment as a treatment option for acute hypertension based on a 20 mm Hg or greater reduction in systolic blood pressure. A retrospective chart review at a large tertiary community teaching hospital was performed on all adult noncardiac inpatients with an episode of acute hypertension that resulted in the administration of nitroglycerin ointment. Seventy-two patients met inclusion criteria with a total of 112 applications of nitroglycerin ointment. Of the 112 applications, systolic blood pressure decreased 20 mm Hg or more in 42% of occurrences with a median decrease of 16 mm Hg. Study results suggest possible efficacy of nitroglycerin ointment for the treatment of acute hypertension in noncardiac hospitalized patients. © The Author(s) 2014.
Effects of acute and chronic cilazapril treatment in spontaneously hypertensive rats

PubMed Central

Fischli, W.; Hefti, F.; Clozel, J.-P.

1989-01-01

1 The effects of acute and chronic treatment with cilazapril, a new ACE inhibitor, on peripheral vasculature and renal excretory function were assessed in spontaneously hypertensive rats. Regional blood flow and cardiac output were measured by the radio-active microspheres technique. 2 Acute treatment (3 mg kg-1 intravenously) reduced mean arterial blood pressure from 171 ± 7 to 140 241 ± 7 mm Hg (P < 0.001), chronic treatment (1 × 10 mg kg-1 day-1 orally for 9 weeks) from 191 ± 5 to 122 ± 3 mm Hg P < 0.001). With both kinds of treatments cardiac output was unchanged. Heart rate was slightly decreased (-9%, P < 0.05) with chronic treatment. Acutely, the main effect of cilazapril was a decrease of the renal vascular resistance (-41%, P < 0.001) associated with an increase of the fraction of the cardiac output distributed to the kidney (+46%, P < 0.001). Chronically, cilazapril decreased regional vascular resistance in most of the peripheral vascular beds except the heart. 3 With a high dose of cilazapril (10 mg kg-1 orally) both acute and chronic treatment increased diuresis (+107% and +92%, P < 0.001) and natriuresis (+124% and +111%, P < 0.001) with a slight increase in kaliuresis. However, with a low dose (1 mg kg-1 orally) the kidneys responded only to chronic treatment. 4 It is concluded that chronic treatment with cilazapril decreases arterial blood pressure more than acute treatment. This effect seems to be due to a greater peripheral vasodilation. In addition, diuretic and natriuretic effects of cilazapril probably contribute to blood pressure reduction. PMID:2527529
Effect of Agomelatine and Fluoxetine on HAM-D Score, Serum Brain-Derived Neurotrophic Factor, and Tumor Necrosis Factor-α Level in Patients With Major Depressive Disorder With Severe Depression.

PubMed

Gupta, Keshav; Gupta, Rachna; Bhatia, M S; Tripathi, A K; Gupta, Lalit K

2017-12-01

Evidence suggests that neurotrophic factors, inflammatory markers, and circadian rhythm dysfunctions could be involved in pathophysiology of major depressive disorder. This study evaluated the efficacy and tolerability of agomelatine, a melatonergic drug, and fluoxetine (positive comparator) and their effect on serum brain-derived neurotrophic factor (BDNF) and tumor necrosis factor (TNF)-α level in patients having major depressive disorder with severe depression. In the present study, we chose TNF-α and BDNF because reduction of TNF-α and rise in BDNF levels are linked with improvement in major depressive disorder. Patients with Hamilton Rating Scale for Depression (HAM-D) score ≥25 were treated with agomelatine or fluoxetine and followed up for 12 weeks. In the agomelatine group, the HAM-D score, BDNF level, and TNF-α level at the start of treatment were 31.1 ± 1.88 ng/mL, 2.44 ± 0.38 ng/mL, and 512.5 ± 86.2 pg/mL, respectively, which significantly changed to 13.67 ± 2.22 ng/mL, 2.87 ± 0.44 ng/mL, and 391.64 ± 104.8 pg/mL, respectively (P < .05 for all 3 measures), at 12 weeks. In the fluoxetine group, the HAM-D score, BDNF level, and TNF-α level at the start of treatment were 30.83 ± 2.60 ng/mL, 2.54 ± 0.37 ng/mL, and 554.14 ± 46.8 pg/mL, respectively, which significantly changed to 13.67 ± 1.79 ng/mL, 3.07 ± 0.33 ng/mL, and 484.15 ± 49.9 pg/mL, respectively (P < .05 for all 3 measures) at 12 weeks. The BDNF level was significantly increased posttreatment with both drugs, and TNF-α level fell significantly more with agomelatine compared to fluoxetine. Thus, chronic neuroinflammatory biomarkers contribute to circuitry dysregulation in depression. Trophic factors repair dysfunctional circuits in depression. Both treatments were found to be safe and well tolerated. © 2017, The American College of Clinical Pharmacology.

Fluoxetine protects against methamphetamine‑induced lung inflammation by suppressing oxidative stress through the SERT/p38 MAPK/Nrf2 pathway in rats.

PubMed

Wang, Yun; Gu, Yu-Han; Liu, Ming; Bai, Yang; Wang, Huai-Liang

2017-02-01

Methamphetamine (MA) abuse is a major public health and safety concern throughout the world and a growing burden on healthcare costs. The purpose of the present study was to investigate the protective effect of fluoxetine against MA‑induced chronic pulmonary inflammation and to evaluate the potential role of nuclear factor erythroid 2-related factor 2 (Nrf2)-mediated antioxidative stress. Wistar rats were divided into control, MA and two fluoxetine‑treated groups. Rats in the MA and the two fluoxetine‑treated groups were treated daily with intraperitoneal injection of 10 mg/kg MA twice daily. Rats in the two fluoxetine‑treated groups were injected intragastrically with fluoxetine (2 and 10 mg/kg) once daily, respectively. After 5 weeks, the rats were euthanized and hematoxylin and eosin staining, immunohistochemistry, western blot analysis and redox assay were performed. It was demonstrated that chronic exposure to MA can induce pulmonary inflammation in rats, with the symptoms of inflammatory cell infiltration, crowded lung parenchyma, thickened septum and a reduced number of alveolar sacs. Fluoxetine attenuated pulmonary inflammation and the expression of interleukin‑6 and tumor necrosis factor‑α in rat lungs. Fluoxetine inhibited MA‑induced increases in the expression levels of serotonin transporter (SERT) and p‑p38 mitogen‑activated protein kinase (MAPK), and reversed the MA‑induced decrease in nuclear Nrf2 and human heme oxygenase‑1 in lungs. Fluoxetine at 10 mg/kg significantly reversed the reduced glutathione (GSH) level, the ratio of GSH/oxidized glutathione, and the reactive oxygen species level in rat lungs from the MA group. These findings suggested that fluoxetine, a SERT inhibitor, has a protective effect against MA‑induced lung inflammation by suppressing oxidative stress through the SERT/p38 MAPK/Nrf2 pathway in rats.
Comparative efficacy and acceptability of 21 antidepressant drugs for the acute treatment of adults with major depressive disorder: a systematic review and network meta-analysis.

PubMed

Cipriani, Andrea; Furukawa, Toshi A; Salanti, Georgia; Chaimani, Anna; Atkinson, Lauren Z; Ogawa, Yusuke; Leucht, Stefan; Ruhe, Henricus G; Turner, Erick H; Higgins, Julian P T; Egger, Matthias; Takeshima, Nozomi; Hayasaka, Yu; Imai, Hissei; Shinohara, Kiyomi; Tajika, Aran; Ioannidis, John P A; Geddes, John R

2018-04-07

Major depressive disorder is one of the most common, burdensome, and costly psychiatric disorders worldwide in adults. Pharmacological and non-pharmacological treatments are available; however, because of inadequate resources, antidepressants are used more frequently than psychological interventions. Prescription of these agents should be informed by the best available evidence. Therefore, we aimed to update and expand our previous work to compare and rank antidepressants for the acute treatment of adults with unipolar major depressive disorder. We did a systematic review and network meta-analysis. We searched Cochrane Central Register of Controlled Trials, CINAHL, Embase, LILACS database, MEDLINE, MEDLINE In-Process, PsycINFO, the websites of regulatory agencies, and international registers for published and unpublished, double-blind, randomised controlled trials from their inception to Jan 8, 2016. We included placebo-controlled and head-to-head trials of 21 antidepressants used for the acute treatment of adults (≥18 years old and of both sexes) with major depressive disorder diagnosed according to standard operationalised criteria. We excluded quasi-randomised trials and trials that were incomplete or included 20% or more of participants with bipolar disorder, psychotic depression, or treatment-resistant depression; or patients with a serious concomitant medical illness. We extracted data following a predefined hierarchy. In network meta-analysis, we used group-level data. We assessed the studies' risk of bias in accordance to the Cochrane Handbook for Systematic Reviews of Interventions, and certainty of evidence using the Grading of Recommendations Assessment, Development and Evaluation framework. Primary outcomes were efficacy (response rate) and acceptability (treatment discontinuations due to any cause). We estimated summary odds ratios (ORs) using pairwise and network meta-analysis with random effects. This study is registered with PROSPERO, number CRD
Lithium Treatment of Acute Mania in Adolescents: A Placebo-Controlled Discontinuation Study

ERIC Educational Resources Information Center

Kafantaris, Vivian; Coletti, Daniel J.; Dicker, Robert; Padula, Gina; Pleak, Richard R.; Alvir, Jose Ma. J.; Kane, John M.

2004-01-01

Objective: There are no published placebo-controlled studies of any agent in the treatment of acute mania in children or adolescents. This is the first placebo-controlled study of lithium's efficacy in the treatment of acute mania in adolescents. Method: In this discontinuation study, participants received open treatment with lithium at…
Developmental fluoxetine exposure increases behavioral despair and alters epigenetic regulation of the hippocampal BDNF gene in adult female offspring.

PubMed

Boulle, Fabien; Pawluski, Jodi L; Homberg, Judith R; Machiels, Barbie; Kroeze, Yvet; Kumar, Neha; Steinbusch, Harry W M; Kenis, Gunter; van den Hove, Daniel L A

2016-04-01

A growing number of infants are exposed to selective serotonin reuptake inhibitor (SSRI) medications during the perinatal period. Perinatal exposure to SSRI medications alter neuroplasticity and increase depressive- and anxiety-related behaviors, particularly in male offspring as little work has been done in female offspring to date. The long-term effects of SSRI on development can also differ with previous exposure to prenatal stress, a model of maternal depression. Because of the limited work done on the role of developmental SSRI exposure on neurobehavioral outcomes in female offspring, the aim of the present study was to investigate how developmental fluoxetine exposure affects anxiety and depression-like behavior, as well as the regulation of hippocampal brain-derived neurotrophic factor (BDNF) signaling in the hippocampus of adult female offspring. To do this female Sprague-Dawley rat offspring were exposed to prenatal stress and fluoxetine via the dam, for a total of four groups of female offspring: 1) No Stress+Vehicle, 2) No Stress+Fluoxetine, 3) Prenatal Stress+Vehicle, and 4) Prenatal Stress+Fluoxetine. Primary results show that, in adult female offspring, developmental SSRI exposure significantly increases behavioral despair measures on the forced swim test, decreases hippocampal BDNF exon IV mRNA levels, and increases levels of the repressive histone 3 lysine 27 tri-methylated mark at the corresponding promoter. There was also a significant negative correlation between hippocampal BDNF exon IV mRNA levels and immobility in the forced swim test. No effects of prenatal stress or developmental fluoxetine exposure were seen on tests of anxiety-like behavior. This research provides important evidence for the long-term programming effects of early-life exposure to SSRIs on female offspring, particularily with regard to affect-related behaviors and their underlying molecular mechanisms. Copyright © 2016 Elsevier Inc. All rights reserved.
Appropriate treatment of acute sigmoid volvulus in the emergency setting

PubMed Central

Lou, Zheng; Yu, En-Da; Zhang, Wei; Meng, Rong-Gui; Hao, Li-Qiang; Fu, Chuan-Gang

2013-01-01

AIM: To investigate an appropriate strategy for the treatment of patients with acute sigmoid volvulus in the emergency setting. METHODS: A retrospective review of 28 patients with acute sigmoid volvulus treated in the Department of Colorectal Surgery, Changhai Hospital, Shanghai from January 2001 to July 2012 was performed. Following the diagnosis of acute sigmoid volvulus, an initial colonoscopic approach was adopted if there was no evidence of diffuse peritonitis. RESULTS: Of the 28 patients with acute sigmoid volvulus, 19 (67.9%) were male and 9 (32.1%) were female. Their mean age was 63.1 ± 22.9 years (range, 21-93 years). Six (21.4%) patients had a history of abdominal surgery, and 17 (60.7%) patients had a history of constipation. Abdominal radiography or computed tomography was performed in all patients. Colonoscopic detorsion was performed in all 28 patients with a success rate of 92.8% (26/28). Emergency surgery was required in the other two patients. Of the 26 successfully treated patients, seven (26.9%) had recurrent volvulus. CONCLUSION: Colonoscopy is the primary emergency treatment of choice in uncomplicated acute sigmoid volvulus. Emergency surgery is only for patients in whom nonoperative treatment is unsuccessful, or in those with peritonitis. PMID:23946604
Re-evaluating the treatment of acute optic neuritis.

PubMed

Bennett, Jeffrey L; Nickerson, Molly; Costello, Fiona; Sergott, Robert C; Calkwood, Jonathan C; Galetta, Steven L; Balcer, Laura J; Markowitz, Clyde E; Vartanian, Timothy; Morrow, Mark; Moster, Mark L; Taylor, Andrew W; Pace, Thaddeus W W; Frohman, Teresa; Frohman, Elliot M

2015-07-01

Clinical case reports and prospective trials have demonstrated a reproducible benefit of hypothalamic-pituitary-adrenal (HPA) axis modulation on the rate of recovery from acute inflammatory central nervous system (CNS) demyelination. As a result, corticosteroid preparations and adrenocorticotrophic hormones are the current mainstays of therapy for the treatment of acute optic neuritis (AON) and acute demyelination in multiple sclerosis.Despite facilitating the pace of recovery, HPA axis modulation and corticosteroids have failed to demonstrate long-term benefit on functional recovery. After AON, patients frequently report visual problems, motion perception difficulties and abnormal depth perception despite 'normal' (20/20) vision. In light of this disparity, the efficacy of these and other therapies for acute demyelination require re-evaluation using modern, high-precision paraclinical tools capable of monitoring tissue injury.In no arena is this more amenable than AON, where a new array of tools in retinal imaging and electrophysiology has advanced our ability to measure the anatomic and functional consequences of optic nerve injury. As a result, AON provides a unique clinical model for evaluating the treatment response of the derivative elements of acute inflammatory CNS injury: demyelination, axonal injury and neuronal degeneration.In this article, we examine current thinking on the mechanisms of immune injury in AON, discuss novel technologies for the assessment of optic nerve structure and function, and assess current and future treatment modalities. The primary aim is to develop a framework for rigorously evaluating interventions in AON and to assess their ability to preserve tissue architecture, re-establish normal physiology and restore optimal neurological function. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.
Age-related changes in the antidepressant-like effect of desipramine and fluoxetine in the rat forced-swim test.

PubMed

Olivares-Nazario, Maribel; Fernández-Guasti, Alonso; Martínez-Mota, Lucía

2016-02-01

Some reports suggest that older patients are less responsive to antidepressants than young adults, but this idea has not been fully supported. Here, we investigated the role of aging in the behavioral effects of the antidepressants, desipramine (DMI) (5, 10, and 20 mg/kg) and fluoxetine (FLX) (5, 10, and 20 mg/kg) in young adults (3-5 months), middle-aged (MA, 12-15 months), and senescent (SE, 23-25 months) male rats in the forced-swim test. In addition, locomotor activity and motor coordination were assessed as side-effects. DMI and fluoxetine produced an antidepressant-like effect in YA and MA animals, although in the latter group, a shift to the right in the dose-response curve was found for DMI. Importantly, neither drug was effective in SE animals. Motor side-effects were produced mainly by DMI in MA and SE rats. Therefore, a decrease in the antidepressant-like effect is associated strongly with senescence as well as an increased vulnerability to motor side-effects, particularly of tricyclics. This study is significant because SE animals are scarcely studied in pharmacological screening tests, and our findings might be useful for improving antidepressant treatments for the increasing aged population.
[Unpredictable chronic mild stress effects on antidepressants activities in forced swim test].

PubMed

Kudryashov, N V; Kalinina, T S; Voronina, T A

2015-02-01

The experiments has been designed to study unpredictable chronic mild stress effect on anti-depressive activities of amitriptyline (10 mg/kg) and fluoxetine (20 mg/kg) in forced swim test in male outbred mice. It is shown that acute treatment with fluoxetine does not produce any antidepressant effects in mice following stress of 14 days while the sub-chronic injections of fluoxetine result in more deep depressive-like behavior. In 28 daily stressed mice, antidepressant effect of fluoxetine is observed independently of the injection rates. Amitriptyline demonstrates the antidepressant activity regardless of the duration of stress or administration scheduling, but at the same time the severity of anti-immobilization effect of amitriptyline in stressed mice is weaker in compare to non-stressed trails. Thus, the injection rates and duration of unpredictable mild chronic stress are the parameters that determine the efficiency of antidepressants in the mouse forced swimming test.
Anti-Candida activity of fluoxetine alone and combined with fluconazole: a synergistic action against fluconazole-resistant strains.

PubMed

Oliveira, Ana S; Gaspar, Carlos A; Palmeira-de-Oliveira, Rita; Martinez-de-Oliveira, José; Palmeira-de-Oliveira, Ana

2014-07-01

The purpose of this work was to determine the antimicrobial activity of fluoxetine, alone and combined with fluconazole, against 29 Candida strains isolated from patients with vulvovaginal candidiasis. MIC and minimum lethal concentration values ranged from 9.8 to 625 μg/ml for all strains tested. The combination of fluconazole with fluoxetine resulted in synergistic activity against six Candida strains, with fractional inhibitory index (FIX) values between 0.15 and 0.31. An indifferent effect was found for the remaining strains, with FIX values between 0.63 and 1. Copyright © 2014, American Society for Microbiology. All Rights Reserved.
Cost-effectiveness analysis of treatments for premenstrual dysphoric disorder.

PubMed

Rendas-Baum, Regina; Yang, Min; Gricar, Joseph; Wallenstein, Gene V

2010-01-01

Premenstrual syndrome (PMS) is reported to affect between 13% and 31% of women. Between 3% and 8% of women are reported to meet criteria for the more severe form of PMS, premenstrual dysphoric disorder (PMDD). Although PMDD has received increased attention in recent years, the cost effectiveness of treatments for PMDD remains unknown. To evaluate the cost effectiveness of the four medications with a US FDA-approved indication for PMDD: fluoxetine, sertraline, paroxetine and drospirenone plus ethinyl estradiol (DRSP/EE). A decision-analytic model was used to evaluate both direct costs (medication and physician visits) and clinical outcomes (treatment success, failure and discontinuation). Medication costs were based on average wholesale prices of branded products; physician visit costs were obtained from a claims database study of PMDD patients and the Agency for Healthcare Research and Quality. Clinical outcome probabilities were derived from published clinical trials in PMDD. The incremental cost-effectiveness ratio (ICER) was calculated using the difference in costs and percentage of successfully treated patients at 6 months. Deterministic and probabilistic sensitivity analyses were used to assess the impact of uncertainty in parameter estimates. Threshold values where a change in the cost-effective strategy occurred were identified using a net benefit framework. Starting therapy with DRSP/EE dominated both sertraline and paroxetine, but not fluoxetine. The estimated ICER of initiating treatment with fluoxetine relative to DRSP/EE was $US4385 per treatment success (year 2007 values). Cost-effectiveness acceptability curves revealed that for ceiling ratios>or=$US3450 per treatment success, fluoxetine had the highest probability (>or=0.37) of being the most cost-effective treatment, relative to the other options. The cost-effectiveness acceptability frontier further indicated that DRSP/EE remained the option with the highest expected net monetary benefit for
Treatment of acute pancreatitis with mexidol and low-intensity laser radiation

NASA Astrophysics Data System (ADS)

Parzyan, G. R.; Geinits, A. V.

2001-04-01

This article presents the results of treatment of 54 patients with acute pancreatitis. The patients were divided into two groups according to the method of treatment. The control group (26 patients) received a conventional therapy, whereas the experimental group (28 patients) received mexidol in combination with the intravenous laser irradiation of blood. Clinical and laboratory tests confirmed a high efficiency of the combined therapy based on the administration of mexidol antioxidant and low-intensity (lambda) equals 0.63 micrometers diode laser irradiation of blood. This therapeutic technique produced an influence on the basic pathogenetic mechanisms of acute pancreatitis. The application of this method of treatment improved the course and prognosis of acute pancreatitis.
Parent Involvement in CBT Treatment of Adolescent Depression: Experiences in the Treatment for Adolescents with Depression Study (TADS)

ERIC Educational Resources Information Center

Wells, Karen C.; Albano, Anne Marie

2005-01-01

The Treatment for Adolescents With Depression Study (TADS) evaluated the short- and long-term effectiveness of cognitive behavior therapy (CBT) alone, fluoxetine alone, and their combination, relative to pill placebo, and the 12-week treatment effects were recently published (TADS Team, 2004). Results showed that treatment that combined CBT with…
Efficacy of individualized homeopathic treatment and fluoxetine for moderate to severe depression in peri- and postmenopausal women (HOMDEP-MENOP): study protocol for a randomized, double-dummy, double-blind, placebo-controlled trial.

PubMed

Macías-Cortés, Emma del Carmen; Aguilar-Faisal, Leopoldo; Asbun-Bojalil, Juan

2013-04-23

The perimenopausal period refers to the interval when women's menstrual cycles become irregular and is characterized by an increased risk of depressive symptoms. Use of homeopathy to treat depression is widespread but there is a lack of clinical trials about its efficacy in depression in peri- and postmenopausal women. Previous trials suggest that individualized homeopathic treatments improve depression. In classical homeopathy, an individually selected homeopathic remedy is prescribed after a complete case history of the patient. The aim of this study is to assess the efficacy and safety of the homeopathic individualized treatment versus placebo or fluoxetine in peri- and postmenopausal women with moderate to severe depression. A randomized, placebo-controlled, double-blind, double-dummy, three-arm trial with a six-week follow-up study was designed. The study will be conducted in a public research hospital in Mexico City (Juárez de México Hospital) in the outpatient service of homeopathy. One hundred eighty nine peri- and postmenopausal women diagnosed with major depression according to the Diagnostic and Statistical Manual of Mental Disorders, 4th edition (moderate to severe intensity) will be included. The primary outcome is change in the mean total score among groups on the 17-item Hamilton Rating Scale for Depression after the fourth and sixth week of treatment. Secondary outcomes are: Beck Depression Inventory change in mean score, Greene's Scale change in mean score, response and remission rates and safety. Efficacy data will be analyzed in the intention-to-treat population. To determine differences in the primary and secondary outcomes among groups at baseline and weeks four and six, data will be analyzed by analysis of variance for independent measures with the Bonferroni post-hoc test. This study is the first trial of classical homeopathy that will evaluate the efficacy of homeopathic individualized treatment using C-potencies versus placebo or
Efficacy of individualized homeopathic treatment and fluoxetine for moderate to severe depression in peri- and postmenopausal women (HOMDEP-MENOP): study protocol for a randomized, double-dummy, double-blind, placebo-controlled trial

PubMed Central

2013-01-01

Background The perimenopausal period refers to the interval when women’s menstrual cycles become irregular and is characterized by an increased risk of depressive symptoms. Use of homeopathy to treat depression is widespread but there is a lack of clinical trials about its efficacy in depression in peri- and postmenopausal women. Previous trials suggest that individualized homeopathic treatments improve depression. In classical homeopathy, an individually selected homeopathic remedy is prescribed after a complete case history of the patient. The aim of this study is to assess the efficacy and safety of the homeopathic individualized treatment versus placebo or fluoxetine in peri- and postmenopausal women with moderate to severe depression. Methods/design A randomized, placebo-controlled, double-blind, double-dummy, three-arm trial with a six-week follow-up study was designed. The study will be conducted in a public research hospital in Mexico City (Juárez de México Hospital) in the outpatient service of homeopathy. One hundred eighty nine peri- and postmenopausal women diagnosed with major depression according to the Diagnostic and Statistical Manual of Mental Disorders, 4th edition (moderate to severe intensity) will be included. The primary outcome is change in the mean total score among groups on the 17-item Hamilton Rating Scale for Depression after the fourth and sixth week of treatment. Secondary outcomes are: Beck Depression Inventory change in mean score, Greene’s Scale change in mean score, response and remission rates and safety. Efficacy data will be analyzed in the intention-to-treat population. To determine differences in the primary and secondary outcomes among groups at baseline and weeks four and six, data will be analyzed by analysis of variance for independent measures with the Bonferroni post-hoc test. Discussion This study is the first trial of classical homeopathy that will evaluate the efficacy of homeopathic individualized treatment
Treatment of acute diarrhea with Saccharomyces boulardii in infants.

PubMed

Corrêa, Naflesia B O; Penna, Francisco J; Lima, Fátima M L S; Nicoli, Jacques R; Filho, Luciano A P

2011-11-01

The aim of the study was to determine whether an oral treatment with a commercial pharmaceutical product containing Saccharomyces boulardii would reduce the duration of diarrhea in infants with acute diarrhea. In the present double-blind, placebo-controlled study, 186 infants, 6 to 48 months old and hospitalized within 72 hours after the onset of acute diarrhea in 2 hospitals in Goiânia, Goiás, Brazil, were randomly assigned to receive twice per day for 5 days 200 mg of a commercial pharmaceutical product containing 4 × 10 viable cells of S boulardii or a placebo. Stool samples were submitted to search for rotavirus. Among the 176 infants who completed the trial, those treated with S boulardii (90) showed a reduction in diarrhea duration (P < 0.05) when compared with the placebo group (86). The present study shows a reduction in diarrhea duration when S boulardii was given to children within 72 hours after the onset of acute diarrhea. The present study suggests a complementary treatment of acute diarrhea in infants with daily oral doses of S boulardii.
[System evaluation on Ginkgo Biloba extract in the treatment of acute cerebral infarction].

PubMed

Wang, Lin; Zhang, Tao; Bai, Kezhen

2015-10-01

To evaluate the effect and safety of Ginkgo Biloba extract on the treatment of acute cerebral infarction.  The Database of Wanfang, China National Knowledge Infrastructure (CNKI) and VIPU were screened for literatures regarding Ginkgo Biloba extract in the treatment of acute cerebral infarction, including the clinical randomized controlled trials. Meta-analysis based on the Revman 4.2 system was performed.  Compared with the control group, treatment with Ginkgo Biloba extract enhanced efficacy in the treatment of acute cerebral infarction (OR: 1.60-5.53), which displayed an improved neural function defect score [WMD -3.12 (95%CI: -3.96- -2.28)].  Ginkgo Biloba extract is beneficial to the improvement of neurological function in patients with acute cerebral infarction and it is safe for patients.
Problem-solving ability and comorbid personality disorders in depressed outpatients.

PubMed

Harley, Rebecca; Petersen, Timothy; Scalia, Margaret; Papakostas, George I; Farabaugh, Amy; Fava, Maurizio

2006-01-01

Major depressive disorder (MDD) is associated with poor problem-solving abilities. In addition, certain personality disorders (PDs) that are common among patients with MDD are also associated with limited problem-solving skills. Attempts to understand the relationship between PDs and problem solving can be complicated by the presence of acute MDD. Our objective in this study was to investigate the relationships between PDs, problem-solving skills, and response to treatment among outpatients with MDD. We enrolled 312 outpatients with MDD in an open, fixed-dose, 8-week fluoxetine trial. PD diagnoses were ascertained via structured clinical interview before and after fluoxetine treatment. Subjects completed the Problem-Solving Inventory (PSI) at both time points. We used analyses of covariance (ANCOVAs) to assess relationships between PD diagnoses and PSI scores prior to treatment. Subjects were divided into three groups: those with PD diagnoses that remained stable after fluoxetine treatment (N=91), those who no longer met PD criteria after fluoxetine treatment (N=119), and those who did not meet criteria for a PD at any time point in the study (N=95). We used multiple chi(2) analyses to compare rates of MDD response and remission between the three PD groups. ANCOVA was also used to compare posttreatment PSI scores between PD groups. Prior to fluoxetine treatment, patients with avoidant, dependent, narcissistic, and borderline PDs reported significantly worse problem-solving ability than did patients without any PDs. Only subjects with dependent PD remained associated with poorer baseline problem-solving reports after the effects of baseline depression severity were controlled. Patients with stable PD diagnoses had significantly lower rates of MDD remission. Across PD groups, problem solving improved as MDD improved. No significant differences in posttreatment problem-solving were found between PD groups after controlling for baseline depression severity, baseline
Treatment-Resistant Depressed Youth Show a Higher Response Rate If Treatment Ends during Summer School Break

ERIC Educational Resources Information Center

Shamseddeen, Wael; Clarke, Gregory; Wagner, Karen Dineen; Ryan, Neal D.; Birmaher, Boris; Emslie, Graham; Asarnow, Joan Rosenbaum; Porta, Giovanna; Mayes, Taryn; Keller, Martin B.; Brent, David A.

2011-01-01

Objective: There is little work on the effect of school on response to treatment of depression, with available research suggesting that children and adolescents with school difficulties are less likely to respond to fluoxetine compared with those with no school difficulties. Method: Depressed adolescents in the Treatment of Resistant Depression in…
Outcomes after treatment of acute aortic occlusion.

PubMed

de Varona Frolov, Serguei R; Acosta Silva, Marcela P; Volo Pérez, Guido; Fiuza Pérez, Maria D

2015-11-01

Acute aortic occlusion (AAO) is a rare disease with high morbidity and mortality. The aim of this study was to describe the results of surgical treatment of acute aortic occlusion and risk factors for mortality. Retrospective review of the clinical history of 29 patients diagnosed and operated on for AAO during 28 years. The following variables were analysed: age, sex, tabaco use, diabetes, chronic renal insufficiency, chronic heart failure, atrial fibrillation, arterial hypertension, symptoms, diagnosis and treatment, 30-day mortality and long-term survival. A univariant analysis was performed of variables related to mortality. Twenty-nine patients were included (18 male) with a mean age of 66,2 years. The aetiology was: embolism (EM) in 11 cases and Thrombosis (TR) in 18 cases. The surgical procedures performed included bilateral transfemoral thrombectomy (14 cases), aorto-bifemoral by-pass (8 cases), axilo uni/bifemoral by-pass (5 cases) and aortoiliac and renal tromboendarterectomy (2 cases). Morbidity included: renal failure (14 cases), mesenteric ischemia (4 cases), cardiac complications (7 cases), respiratory complications (5 cases) and loss of extremity (2 cases). The in-hospital mortality was 21% (EM 0%, TR 21%). The estimated survival at 1.3 and 5 years was 60, 50 and 44% respectively. Age (p=0.032), arterial hypertension (p=0.039) and aetiology of the AAO (p=0.039) were related to mortality. Acute aortic occlusion is a medical emergency with high mortality rates. Acute renal failure is the most common postoperative complication. Copyright © 2012 AEC. Publicado por Elsevier España, S.L.U. All rights reserved.
Remission and Residual Symptoms after Short-Term Treatment in the Treatment of Adolescents with Depression Study (TADS)

ERIC Educational Resources Information Center

Kennard, Betsy; Silva, Susan; Vitiello, Benedetto; Curry, John; Kratochvil, Christopher; Simons, Anne; Hughes, Jennifer; Feeny, Norah; Weller, Elizabeth; Sweeney, Michael; Reinecke, Mark; Pathak, Sanjeev; Ginsburg, Golda; Emslie, Graham; March, John

2006-01-01

Objective: To ascertain remission rates in depressed youth participating in the Treatment for Adolescents With Depression Study (TADS), a multisite clinical trial that randomized 439 adolescents with major depressive disorder (MDD) to a 12-week treatment of fluoxetine (FLX), cognitive-behavioral therapy (CBT), their combination (COMB), or clinical…

Ineffective acute treatment of episodic migraine is associated with new-onset chronic migraine.

PubMed

Lipton, Richard B; Fanning, Kristina M; Serrano, Daniel; Reed, Michael L; Cady, Roger; Buse, Dawn C

2015-02-17

To test the hypothesis that ineffective acute treatment of episodic migraine (EM) is associated with an increased risk for the subsequent onset of chronic migraine (CM). In the American Migraine Prevalence and Prevention Study, respondents with EM in 2006 who completed the Migraine Treatment Optimization Questionnaire (mTOQ-4) and provided outcome data in 2007 were eligible for analyses. The mTOQ-4 is a validated questionnaire that assesses treatment efficacy based on 4 aspects of response to acute treatment. Total mTOQ-4 scores were used to define categories of acute treatment response: very poor, poor, moderate, and maximum treatment efficacy. Logistic regression models were used to examine the dichotomous outcome of transition from EM in 2006 to CM in 2007 as a function of mTOQ-4 category, adjusting for covariates. Among 5,681 eligible study respondents with EM in 2006, 3.1% progressed to CM in 2007. Only 1.9% of the group with maximum treatment efficacy developed CM. Rates of new-onset CM increased in the moderate treatment efficacy (2.7%), poor treatment efficacy (4.4%), and very poor treatment efficacy (6.8%) groups. In the fully adjusted model, the very poor treatment efficacy group had a more than 2-fold increased risk of new-onset CM (odds ratio = 2.55, 95% confidence interval 1.42-4.61) compared to the maximum treatment efficacy group. Inadequate acute treatment efficacy was associated with an increased risk of new-onset CM over the course of 1 year. Improving acute treatment outcomes might prevent new-onset CM, although reverse causality cannot be excluded. © 2015 American Academy of Neurology.
Guidelines for the treatment of acute ischaemic stroke.

PubMed

Alonso de Leciñana, M; Egido, J A; Casado, I; Ribó, M; Dávalos, A; Masjuan, J; Caniego, J L; Martínez Vila, E; Díez Tejedor, E; Fuentes, B; Álvarez-Sabin, J; Arenillas, J; Calleja, S; Castellanos, M; Castillo, J; Díaz-Otero, F; López-Fernández, J C; Freijo, M; Gállego, J; García-Pastor, A; Gil-Núñez, A; Gilo, F; Irimia, P; Lago, A; Maestre, J; Martí-Fábregas, J; Martínez-Sánchez, P; Molina, C; Morales, A; Nombela, F; Purroy, F; Rodríguez-Yañez, M; Roquer, J; Rubio, F; Segura, T; Serena, J; Simal, P; Tejada, J; Vivancos, J

2014-03-01

Update of Acute Ischaemic Stroke Treatment Guidelines of the Spanish Neurological Society based on a critical review of the literature. Recommendations are made based on levels of evidence from published data and studies. Organized systems of care should be implemented to ensure access to the optimal management of all acute stroke patients in stroke units. Standard of care should include treatment of blood pressure (should only be treated if values are over 185/105 mmHg), treatment of hyperglycaemia over 155 mg/dl, and treatment of body temperature with antipyretic drugs if it rises above 37.5 °C. Neurological and systemic complications must be prevented and promptly treated. Decompressive hemicraniectomy should be considered in cases of malignant cerebral oedema. Intravenous thrombolysis with rtPA should be administered within 4.5 hours from symptom onset, except when there are contraindications. Intra-arterial pharmacological thrombolysis can be considered within 6 hours, and mechanical thrombectomy within 8 hours from onset, for anterior circulation strokes, while a wider window of opportunity up to 12-24 hours is feasible for posterior strokes. There is not enough evidence to recommend routine use of the so called neuroprotective drugs. Anticoagulation should be administered to patients with cerebral vein thrombosis. Rehabilitation should be started as early as possible. Treatment of acute ischaemic stroke includes management of patients in stroke units. Systemic thrombolysis should be considered within 4.5 hours from symptom onset. Intra-arterial approaches with a wider window of opportunity can be an option in certain cases. Protective and restorative therapies are being investigated. Copyright © 2011 Sociedad Española de Neurología. Published by Elsevier Espana. All rights reserved.
SSRI-induced sexual dysfunction: fluoxetine, paroxetine, sertraline, and fluvoxamine in a prospective, multicenter, and descriptive clinical study of 344 patients.

PubMed

Montejo-González, A L; Llorca, G; Izquierdo, J A; Ledesma, A; Bousoño, M; Calcedo, A; Carrasco, J L; Ciudad, J; Daniel, E; De la Gandara, J; Derecho, J; Franco, M; Gomez, M J; Macias, J A; Martin, T; Perez, V; Sanchez, J M; Sanchez, S; Vicens, E

1997-01-01

The authors analyzed the incidence of sexual dysfunction (SD) with different selective serotonin reuptake inhibitors (SSRIs; fluoxetine, fluvoxamine, paroxetine, and sertraline) and hence the qualitative and quantitative changes in SD throughout time in a prospective and multicenter study. Outpatients (192 women and 152 men; age = 39.6 +/- 11.4 years) under treatment with SSRIs were interviewed with an SD questionnaire designed for this purpose by the authors and that included questions about the following: decreased libido, delayed orgasm or anorgasmia, delayed ejaculation, inability to ejaculate, impotence, and general sexual satisfaction. Patients with the following criteria were included: normal sexual function before SSRI intake, exclusive treatment with SSRIs or treatment associated with benzodiazepines, previous heterosexual or self-erotic current sexual practices. Excluded were patients with previous sexual dysfunction, association of SSRIs with neuroleptics, recent hormone intake, and significant medical illnesses. There was a significant increase in the incidence of SD when physicians asked the patients direct questions (58%) versus when SD was spontaneously reported (14%). There were some significant differences among different SSRIs: paroxetine provoked more delay of orgasm or ejaculation and more impotence than fluvoxamine, fluoxetine and sertraline (chi 2, p < .05). Only 24.5% of the patients had a good tolerance of their sexual dysfunction. Twelve male patients who suffered from premature ejaculation before the treatment preferred to maintain delayed ejaculation, and their sexual satisfaction, and that of their partners, clearly improved. Sexual dysfunction was positively correlated with dose. Patients experienced substantial improvement in sexual function when the dose was diminished or the drug was withdrawn. Men showed more incidence of sexual dysfunction than women, but women's sexual dysfunction was more intense than men's. In only 5.8% of
Ketamine treatment involves medial prefrontal cortex serotonin to induce a rapid antidepressant-like activity in BALB/cJ mice.

PubMed

Pham, T H; Mendez-David, I; Defaix, C; Guiard, B P; Tritschler, L; David, D J; Gardier, A M

2017-01-01

Unlike classic serotonergic antidepressant drugs, ketamine, an NMDA receptor antagonist, exhibits a rapid and persistent antidepressant (AD) activity, at sub-anaesthetic doses in treatment-resistant depressed patients and in preclinical studies in rodents. The mechanisms mediating this activity are unclear. Here, we assessed the role of the brain serotonergic system in the AD-like activity of an acute sub-anaesthetic ketamine dose. We compared ketamine and fluoxetine responses in several behavioral tests currently used to predict anxiolytic/antidepressant-like potential in rodents. We also measured their effects on extracellular serotonin levels [5-HT] ext in the medial prefrontal cortex (mPFCx) and brainstem dorsal raphe nucleus (DRN), a serotonergic nucleus involved in emotional behavior, and on 5-HT cell firing in the DRN in highly anxious BALB/cJ mice. Ketamine (10 mg/kg i.p.) had no anxiolytic-like effect, but displayed a long lasting AD-like activity, i.e., 24 h post-administration, compared to fluoxetine (18 mg/kg i.p.). Ketamine (144%) and fluoxetine (171%) increased mPFCx [5-HT] ext compared to vehicle. Ketamine-induced AD-like effect was abolished by a tryptophan hydroxylase inhibitor, para-chlorophenylalanine (PCPA) pointing out the role of the 5-HT system in its behavioral activity. Interestingly, increase in cortical [5-HT] ext following intra-mPFCx ketamine bilateral injection (0.25 μg/side) was correlated with its AD-like activity as measured on swimming duration in the FST in the same mice. Furthermore, pre-treatment with a selective AMPA receptor antagonist (intra-DRN NBQX) blunted the effects of intra-mPFCx ketamine on both the swimming duration in the FST and mPFCx [5-HT] ext suggesting that the AD-like activity of ketamine required activation of DRN AMPA receptors and recruited the prefrontal cortex/brainstem DRN neural circuit in BALB/c mice. These results confirm a key role of cortical 5-HT release in ketamine's AD-like activity following
Predictors of mental health-related acute service utilisation and treatment costs in the 12 months following an acute psychiatric admission.

PubMed

Siskind, Dan; Harris, Meredith; Diminic, Sandra; Carstensen, Georgia; Robinson, Gail; Whiteford, Harvey

2014-11-01

A key step in informing mental health resource allocation is to identify the predictors of service utilisation and costs. This project aims to identify the predictors of mental health-related acute service utilisation and treatment costs in the year following an acute public psychiatric hospital admission. A dataset containing administrative and routinely measured outcome data for 1 year before and after an acute psychiatric admission for 1757 public mental health patients was analysed. Multivariate regression models were developed to identify patient- and treatment-related predictors of four measures of service utilisation or cost: (a) duration of index admission; and, in the year after discharge from the index admission (b) acute psychiatric inpatient bed-days; (c) emergency department (ED) presentations; and (d) total acute mental health service costs. Split-sample cross-validation was used. A diagnosis of psychosis, problems with living conditions and prior acute psychiatric inpatient bed-days predicted a longer duration of index admission, while prior ED presentations and self-harm predicted a shorter duration. A greater number of acute psychiatric inpatient bed-days in the year post-discharge were predicted by psychosis diagnosis, problems with living conditions and prior acute psychiatric inpatient admissions. The number of future ED presentations was predicted by past ED presentations. For total acute care costs, diagnosis of psychosis was the strongest predictor. Illness acuity and prior acute psychiatric inpatient admission also predicted higher costs, while self-harm predicted lower costs. The development of effective models for predicting acute mental health treatment costs using existing administrative data is an essential step towards a workable activity-based funding model for mental health. Future studies would benefit from the inclusion of a wider range of variables, including ethnicity, clinical complexity, cognition, mental health legal status
Treatment Option Overview (Adult Acute Myeloid Leukemia)

MedlinePlus

... in the past. Having had treatment for childhood acute lymphoblastic leukemia (ALL) in the past. Being exposed to radiation from an atomic bomb or to the chemical benzene . Having a history of a blood disorder such as myelodysplastic syndrome . Signs and symptoms of adult AML include fever, ...
Treatment Options for Adult Acute Myeloid Leukemia

MedlinePlus

... in the past. Having had treatment for childhood acute lymphoblastic leukemia (ALL) in the past. Being exposed to radiation from an atomic bomb or to the chemical benzene . Having a history of a blood disorder such as myelodysplastic syndrome . Signs and symptoms of adult AML include fever, ...
Dogs with separation-related problems show a "less pessimistic" cognitive bias during treatment with fluoxetine (Reconcile™) and a behaviour modification plan.

PubMed

Karagiannis, Christos I; Burman, Oliver Hp; Mills, Daniel S

2015-03-28

Canine separation-related problems (SRP) (also described as "separation anxiety" or "separation distress") are among the most common behavioural complaints of dog owners. Treatment with psychoactive medication in parallel with a behaviour modification plan is well documented in the literature, but it is unknown if this is associated with an improvement in underlying affective state (emotion and mood) or simply an inhibition of the behaviour. Cognitive judgement bias tasks have been proposed as a method for assessing underlying affective state and so we used this approach to identify if any change in clinical signs during treatment was associated with a consistent change in cognitive bias (affective state). Five dogs showing signs of SRP (vocalising - e.g. barking, howling-, destruction of property, and toileting - urination or defecation- when alone) were treated with fluoxetine chewable tablets (Reconcile™) and set on a standard behaviour modification plan for two months. Questionnaires and interviews of the owners were used to monitor the clinical progress of the dogs. Subjects were also evaluated using a spatial cognitive bias test to infer changes in underlying affect prior to, and during, treatment. Concurrently, seven other dogs without signs of SRP were tested in the same way to act as controls. Furthermore, possible correlations between cognitive bias and clinical measures were also assessed for dogs with SRP. Prior to treatment, the dogs with SRP responded to ambiguous positions in the cognitive bias test negatively (i.e. with slower running speeds) compared to control dogs (p < 0.05). On weeks 2 and 6 of treatment, SRP dogs displayed similar responses in the cognitive bias test to control dogs, consistent with the possible normalization of affect during treatment, with this effect more pronounced at week 6 (p > 0.05). Questionnaire based clinical measures were significantly correlated among themselves and with performance in the cognitive bias test
[Drug treatment of acute myelogenous leukaemia. Current options and future perspectives].

PubMed

Telek, Béla; Rejtő, László; Batár, Péter; Miltényi, Zsófia; Reményi, Gyula; Simon, Zsófia; Ujj, Zsófia; Mezei, Gabriella; Szász, Róbert; Kiss, Attila; Udvardy, Miklós; Illés, Árpád

2016-05-29

Acute myelogenous leukemia is a heterogeneous disease. Recent molecular mutational analysis techniques have shed more light on different, genetically well characterised types of the disease. Treatment approach is uniform except for acute promyelocytic leukemia. Application of the "3 + 7" induction treatment has been the gold standard in the past 40 years. While the dose of cytarabine has not been changed, escalating daunorubicine dose in younger (<60 years) patients with good performance status to 90 mg/m(2) had a positive impact on overall survival. High dose chemotherapy is tolerated poorly in patients older than 60 years of age and, as treatment is not curative in the elderly, improvement of overall survival and quality of life remains the main goal of management in these patients. Low intensity treatment is beneficial and can provide additional advantage over supportive care. Innovative and targeted therapy approaches might give promise to better management of patients with acute myelogenous leukemia.
A possible participation of transient receptor potential vanilloid type 1 channels in the antidepressant effect of fluoxetine.

PubMed

Manna, Shyamshree S S; Umathe, Sudhir N

2012-06-15

The present study investigated the influence of transient receptor vanilloid type 1 (TRPV1) channel agonist (capsaicin) and antagonist (capsazepine) either alone or in combination with traditional antidepressant drug, fluoxetine; or a serotonin hydroxylase inhibitor, para-chlorophenylalanine; or a glutamate N-methyl-D-aspartate (NMDA) receptor agonist, NMDA on the forced swim test and tail suspension test using male Swiss mice. Results revealed that intracerebroventricular injections of capsaicin (200 and 300 μg/mouse) and capsazepine (100 and 200 μg/mouse) reduced the immobility time, exhibiting antidepressant-like activity that was comparable to the effects of fluoxetine (2.5-10 μg/mouse) in both the tests. However, in the presence of inactive dose (10 μg/mouse) of capsazepine, capsaicin (300 μg/mouse) had no influence on the indices of both tests, signifying that the effects are TRPV1-mediated. Further, the antidepressant-like effects of both the TRPV1 ligands were neutralized in mice-pretreated with NMDA (0.1 μg/mouse), suggestive of the fact that decreased glutamatergic transmission might contribute to the antidepressant-like activity. In addition, co-administration of sub-threshold dose of capsazepine (10 μg/mouse) and fluoxetine (1.75 μg/mouse) produced a synergistic effect in both the tests. In contrast, inactive doses of capsaicin (10 and 100 μg/mouse) partially abolished the antidepressant effect of fluoxetine (10 μg/mouse), while its effect was potentiated by active dose of capsaicin (200 μg/mouse). Moreover, pretreatment of mice with para-chlorophenylalanine (300 mg/kg/day × 3 days, i.p.) attenuated the effects of capsaicin and capsazepine, demonstrating a probable interplay between serotonin and TRPV1, at least in parts. Thus, our data indicate a possible role of TRPV1 in depressive-like symptoms. Copyright © 2012 Elsevier B.V. All rights reserved.
Both exogenous 5-HT and endogenous 5-HT, released by fluoxetine, enhance distension evoked propulsion in guinea-pig ileum in vitro.

PubMed

Gwynne, Rachel M; Clarke, Amanda J; Furness, John B; Bornstein, Joel C

2014-01-01

The roles of 5-HT3 and 5-HT4 receptors in the modulation of intestinal propulsion by luminal application of 5-HT and augmentation of endogenous 5-HT effects were studied in segments of guinea-pig ileum in vitro. Persistent propulsive contractions evoked by saline distension were examined using a modified Trendelenburg method. When 5-HT (30 nM), fluoxetine (selective serotonin reuptake inhibitor; 1 nM), 2-methyl-5-HT (5-HT3 receptor agonist; 1 mM), or RS 67506 (5-HT4 receptor agonist, 1 μM) was infused into the lumen, the pressure needed to initiate persistent propulsive activity fell significantly. A specific 5-HT4 receptor antagonist, SB 207266 (10 nM in lumen), abolished the effects of 5-HT, fluoxetine, and RS 67506, but not those of 2-methyl-5-HT. Granisetron (5-HT3 receptor antagonist; 1 μM in lumen) abolished the effect of 5-HT, fluoxetine, RS 67506, and 2-methyl-5-HT. The NK3 receptor antagonist SR 142801 (100 nM in lumen) blocked the effects of 5-HT, fluoxetine, and 2-methyl-5-HT. SB 207266, granisetron, and SR 142801 had no effect by themselves. Higher concentrations of fluoxetine (100 and 300 nM) and RS 67506 (3 and 10 μM) had no effect on the distension threshold for propulsive contractions. These results indicate that luminal application of exogenous 5-HT, or increased release of endogenous mucosal 5-HT above basal levels, acts to lower the threshold for propulsive contractions in the guinea-pig ileum via activation of 5-HT3 and 5-HT4 receptors and the release of tachykinins. The results further indicate that basal release of 5-HT is insufficient to alter the threshold for propulsive motor activity.
[Current treatment options in acute myeloid leukemia].

PubMed

Heuser, M; Schlenk, R F; Ganser, A

2011-12-01

Genetic aberrations form the basis for diagnostic classification of patients with acute myeloid leukemia (AML) according to the World Health Organization (WHO) classification. Moreover, these aberrations predict response to induction chemotherapy, relapse-free survival, and overall survival of patients with AML. Understanding the pathogenetic role of cytogenetic and molecular changes has led to the development of targeted treatment strategies that require rapid diagnostic assessment of the genetic profile of each patient to select the best treatment available.
Group vs. Individual Treatment for Acute Insomnia: A Pilot Study Evaluating a "One-Shot" Treatment Strategy.

PubMed

Boullin, Pam; Ellwood, Christina; Ellis, Jason G

2016-12-23

Despite undeniable evidence for the efficacy and effectiveness of Cognitive Behaviour Therapy for Insomnia (CBT-I), the potential for its widespread dissemination and implementation has yet to be realised. A suggested reason for this is that traditional CBT-I is considered too burdensome for deployment, in its current form, within the context of where it would be most beneficial-Primary Care. One strategy, aimed to address this, has been to develop briefer versions of CBT-I, whilst another has been to deliver CBT-I in a group format. An alternative has been to attempt to address insomnia during its acute phase with a view to circumventing its progression to chronic insomnia. The aim of the present study was to compare a brief version of CBT-I (one-shot) when delivered individually or in groups to those with acute insomnia. Twenty-eight individuals with acute insomnia (i.e., meeting full DSM-5 criteria for insomnia disorder for less than three months) self-assigned to either a group or individual treatment arm. Treatment consisted of a single one-hour session accompanied by a self-help pamphlet. Subjects completed measures of insomnia severity, anxiety and depression pre-treatment and at one-month post-treatment. Additionally, daily sleep diaries were compared between pre-treatment and at the one-month follow up. There were no significant between group differences in treatment outcome on any sleep or mood measures although those in the group treatment arm were less adherent than those who received individual treatment. Furthermore, the combined (group and individual treatment arms) pre-post test effect size on insomnia symptoms, using the Insomnia Severity Index, was large ( d = 2.27). It appears that group treatment is as efficacious as individual treatment within the context of a "one shot" intervention for individuals with acute insomnia. The results are discussed with a view to integrating one-shot CBT-I in Primary Care.
DoD–NCCAM/NIH Workshop on Acupuncture for Treatment of Acute Pain

PubMed Central

Belard, Jean Louis; Glowa, John; Khalsa, Partap; Weber, Wendy; Huntley, Kristen

2013-01-01

Abstract The Department of Defense (DoD) and the National Center for Complementary and Alternative Medicine (NCCAM) at the National Institutes of Health (NIH) cosponsored a workshop that explored the possible benefits of acupuncture treatment for acute pain. One goal of the workshop was to establish a roadmap to building an evidence base on that would indicate whether acupuncture is helpful for treating active-duty military personnel experiencing acute pain. The workshop highlighted brief presentations on the most current research on acupuncture and acute pain mechanisms. The impact of various modifiers (stress, genetics, population, phenotypes, etc.) on acute pain pathways and response to acupuncture treatment was discussed. Additional presentations focused on common neural mechanisms, an overview of real-world experience with using acupuncture to treat traumatic acute pain, and best tools and methods specific for acupuncture studies. Three breakout groups addressed the gaps, opportunities, and barriers to acupuncture use for acute pain in military and trauma settings. Different models of effectiveness research and optimal research designs for conducting trials in acute traumatic pain were also discussed. PMID:23020611
Prozac in the water: Chronic fluoxetine exposure and predation risk interact to shape behaviors in an estuarine crab.

PubMed

Peters, Joseph R; Granek, Elise F; de Rivera, Catherine E; Rollins, Matthew

2017-11-01

Predators exert considerable top-down pressure on ecosystems by directly consuming prey or indirectly influencing their foraging behaviors and habitat use. Prey is, therefore, forced to balance predation risk with resource reward. A growing list of anthropogenic stressors such as rising temperatures and ocean acidification has been shown to influence prey risk behaviors and subsequently alter important ecosystem processes. Yet, limited attention has been paid to the effects of chronic pharmaceutical exposure on risk behavior or as an ecological stressor, despite widespread detection and persistence of these contaminants in aquatic environments. In the laboratory, we simulated estuarine conditions of the shore crab, Hemigrapsus oregonensis, and investigated whether chronic exposure (60 days) to field-detected concentrations (0, 3, and 30 ng/L) of the antidepressant fluoxetine affected diurnal and nocturnal risk behaviors in the presence of a predator, Cancer productus . We found that exposure to fluoxetine influenced both diurnal and nocturnal prey risk behaviors by increasing foraging and locomotor activity in the presence of predators, particularly during the day when these crabs normally stay hidden. Crabs exposed to fluoxetine were also more aggressive, with a higher frequency of agonistic interactions and increased mortality due to conflicts with conspecifics. These results suggest that exposure to field-detected concentrations of fluoxetine may alter the trade-off between resource acquisition and predation risk among crabs in estuaries. This fills an important data gap, highlighting how intra- and interspecific behaviors are altered by exposure to field concentrations of pharmaceuticals; such data more explicitly identify potential ecological impacts of emerging contaminants on aquatic ecosystems and can aid water quality management.
Adult Acute Myeloid Leukemia Treatment (PDQ®)—Health Professional Version

Cancer.gov

Acute myeloid (myelogenous) leukemia (AML) treatment options include chemotherapy, radiation therapy, stem cell transplant, and other medications. Cytogenetic analysis helps predict treatment outcomes. Get detailed information about AML in this summary for clinicians.
Transient postnatal fluoxetine leads to decreased brain arachidonic acid metabolism and cytochrome P450 4A in adult mice.

PubMed

Ramadan, Epolia; Blanchard, Helene; Cheon, Yewon; Fox, Meredith A; Chang, Lisa; Chen, Mei; Ma, Kaizong; Rapoport, Stanley I; Basselin, Mireille

2014-05-01

Fetal and perinatal exposure to selective serotonin (5-HT) reuptake inhibitors (SSRIs) has been reported to alter childhood behavior, while transient early exposure in rodents is reported to alter their behavior and decrease brain extracellular 5-HT in adulthood. Since 5-HT2A/2C receptor-mediated neurotransmission can involve G-protein coupled activation of cytosolic phospholipase A2 (cPLA2), releasing arachidonic acid (ARA) from synaptic membrane phospholipid, we hypothesized that transient postnatal exposure to fluoxetine would alter brain ARA metabolism in adult mice. Brain ARA incorporation coefficients k* and rates Jin were quantitatively imaged following intravenous [1-(14)C]ARA infusion of unanesthetized adult mice that had been injected daily with fluoxetine (10mg/kg i.p.) or saline during postnatal days P4-P21. Expression of brain ARA metabolic enzymes and other relevant markers also was measured. On neuroimaging, k* and Jin was decreased widely in early fluoxetine- compared to saline-treated adult mice. Of the enzymes measured, cPLA2 activity was unchanged, while Ca(2+)-independent iPLA2 activity was increased. There was a significant 74% reduced protein level of cytochrome P450 (CYP) 4A, which can convert ARA to 20-HETE. Reduced brain ARA metabolism in adult mice transiently exposed to postnatal fluoxetine, and a 74% reduction in CYP4A protein, suggest long-term effects independent of drug presence in brain ARA metabolism, and in CYP4A metabolites. These changes might contribute to reported altered behavior following early SSRI in rodents. Published by Elsevier Ltd.
Microbiology and Treatment of Acute Apical Abscesses

PubMed Central

Rôças, Isabela N.

2013-01-01

SUMMARY Acute apical abscess is the most common form of dental abscess and is caused by infection of the root canal of the tooth. It is usually localized intraorally, but in some cases the apical abscess may spread and result in severe complications or even mortality. The reasons why dental root canal infections can become symptomatic and evolve to severe spreading and sometimes life-threatening abscesses remain elusive. Studies using culture and advanced molecular microbiology methods for microbial identification in apical abscesses have demonstrated a multispecies community conspicuously dominated by anaerobic bacteria. Species/phylotypes commonly found in these infections belong to the genera Fusobacterium, Parvimonas, Prevotella, Porphyromonas, Dialister, Streptococcus, and Treponema. Advances in DNA sequencing technologies and computational biology have substantially enhanced the knowledge of the microbiota associated with acute apical abscesses and shed some light on the etiopathogeny of this disease. Species richness and abundance and the resulting network of interactions among community members may affect the collective pathogenicity and contribute to the development of acute infections. Disease modifiers, including transient or permanent host-related factors, may also influence the development and severity of acute abscesses. This review focuses on the current evidence about the etiology and treatment of acute apical abscesses and how the process is influenced by host-related factors and proposes future directions in research, diagnosis, and therapeutic approaches to deal with this disease. PMID:23554416
Plasma BDNFs level initially and post treatment in acute mania: comparison between ECT and atypical antipsychotic treatment and healthy controls.

PubMed

Karamustafalioglu, Nesrin; Genc, Abdullah; Kalelioglu, Tevfik; Tasdemir, Akif; Umut, Gokhan; Incir, Said; Akkuş, Mustafa; Emul, Murat

2015-08-01

Inconsistent findings concerning brain-derived neurotrophic factor (BDNF) levels across different episodes in bipolar disorder have been reported, which is also in line with the treatment effects on BDNF levels in acute mania. We aimed to compare plasma BDNF level alterations after pure antipsychotic drug or ECT plus antipsychotic drug treatment in acute mania. Sixty-eight patients with mania were divided into two treatment arms: the antipsychotic treatment arm (AP) and electroconvulsive therapy (ECT)+AP arm. In addition, 30 healthy controls were included in the study. There was no significant statistical difference according to mean age, education level, marital and working status between patients and healthy controls. The initial serum BDNF level in patients with acute mania was significantly lower than healthy controls. The initial BDNF level between the ECT arm and AP arm was not significant. The BDNF level decreased significantly after reaching remission in patients with acute mania. The change in BDNF level in the AP arm was not significant while in the ECT arm it was significant after treatment. In this study, for the first time we revealed a significant decrease in BDNF levels after ECT sessions in acute manic patients. Besides clinical remission after treatment in acute mania, the decrement in BDNF levels does not seem to be related to clinical response. Thus cumulative effects of mood episodes for the ongoing decrease in BDNF levels might be borne in mind despite the achievement of remission and/or more time being required for an increase in BDNF levels after treatment. © The Author(s) 2015.
Adult Acute Lymphoblastic Leukemia Treatment (PDQ®)—Health Professional Version

Cancer.gov

Adult acute lymphoblastic leukemia (ALL) treatment options include chemotherapy, radiation therapy, stem cell transplant, and targeted therapy. Get detailed information about the molecular genetics, prognosis, and treatment of ALL in this summary for clinicians.

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