SSRIs/selective serotonin reuptake inhibitor

On the basis of both in vitro and in vivo experiments fluvoxamine has been characterized as a potential anti-depressant drug with almost exclusively 5-hydroxytryptamine (5-HT) uptake inhibiting properties. Fluvoxamine is effective in inhibiting 5-ht uptake by blood platelets and brain synaptosomes. Due to inhibition of the membrane pump the compound prevents 5-HT depletion by the tyramine-derivatives H 75/12 and H 77/77. As a result of the interference with the neuronal re-uptake mechanism for 5-HT, fluvoxamine produces a decreased 5-HT turnover in the brain[3].

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In vitro activity: Fluvoxamine elevates [DA]ex levels in the striatum and raises [5-HT]ex levels in the rat prefrontal cortex and thalamus.[1] Through its action on 5-HT neurons or spinal 5-HT2A/2C receptors, fluvoxamine maleate reduces tactile allodynia.[2]

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Flv/Fluvoxamine toxicity on SK-N-SH cells [4]
The toxicity of Flv on SK-N-SH cells was examined using an MTS assay. We used 10, 25, 50, 75, or 100 μg/ml Flv or a vehicle control to treat SK-N-SH cells. SK-N-SH cells treated with Flv showed 80% (25 μg/ml), 29% (50 μg/ml), 19% (75 μg/ml), and 18% (100 μg/ml) viability compared to the vehicle control cells ([p<0.001] at all doses) (Fig. 1). However, SK-N-SH cells treated with 10 μg/ml Flv did not show reduced viability (102%) compared to the vehicle control (Fig. 1). Based on these data, we used 10 μg/ml Flv in all subsequent experiments.

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Flv/Fluvoxamine alleviates Px-induced ER stress mediated apoptosis [4]
Next we investigated whether Flv could alleviate Px-induced ER stress-mediated apoptosis in SK-N-SH cells by monitoring CHOP, cleaved caspase 4, and cleaved caspase 3, an active form of each caspase. CHOP, cleaved caspase 4, and cleaved caspase 3 were induced in cells treated with Px compared to control cells (Fig. 2a–c, [p<0.01] at each comparison), which is consistent with our previous report [19], On the other hand, when cells were pre-treated with Flv followed by co-treatment with Px/Flv for 24 h, the induction of CHOP, cleaved caspase 4 and cleaved caspase 3 were alleviated compared to the Flv-untreated cells (Fig. 2a–c, p<0.05, p<0.05, and p<0.01, respectively). We next investigated the induction of Sig-1R by Flv in SK-N-SH cells. Flv has been reported not only as a potent Sig-1R agonist with stronger affinity than other SSRIs [27], but also as an inducer of Sig-1R [26]. Sig-1R was induced in cells treated with Flv for 12 h compared to untreated cells (Fig. 2d, p<0.05). This induction continued for at least 24 h (Fig. 2e, p<0.01).

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Flv/Fluvoxamine alleviates Px-induced neurotoxicity through Sig-1R [4]
Finally, using a MTS assay, we quantitatively assessed whether Flv can alleviate Px-induced neurotoxicity. Similar to the results from Western blots, the viability that was decreased by Px treatment was recovered in Flv-pre-treated cells compared to Flv-untreated cells (Fig. 3, p<0.05). This recovery was reversed when cells were incubated with Px, Flv and NE100 (Fig. 3, p<0.05).

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We recently reported that Fluvoxamine (Flv) alleviates ER stress via induction of sigma-1 receptor (Sig-1R). The purpose of this study was to investigate whether Flv could alleviate Px-induced neurotoxicity in vitro. SK-N-SH cells were pre-treated for 12 h with or without 10 μg/ml Flv followed by treatment with 1 μM Px with or without co-existence of 10 μg/ml Flv for 24 h. To investigate the involvement of Sig-1R in alleviation effect on Px-induced neurotoxicity,1 μM NE100, an antagonist of Sig-1R, was added for 24 h. Neurotoxicity was assessed using the MTS viability assay and ER stress-mediated neurotoxicity was assessed by evaluating the expression of C/EBP homologous protein (CHOP), cleaved caspase 4, and cleaved caspase 3. Pre-treatment with Flv significantly alleviated the induction of CHOP, cleaved caspase 4, and cleaved caspase 3 in SK-N-SH cells. At the same time, pre-treatment with Flv significantly induced Sig-1R in SK-N-SH cells. In addition, viability was significantly higher in Flv-treated cells than in untreated cells, which was reversed by treatment with NE100. Our results suggest that Flv alleviates Px-induced neurotoxicity in part through the induction of Sig-1R. Our findings should contribute to one of the novel approaches for the alleviation of Px-induced neurotoxicity, including chemobrain [4].

In solution 5-HT, fluvoxamine (DU-23000) efficiently suppresses brain synaptosomes and synaptosomes. It is believed that effects on 5-HT foods account for the solitary antagonistic impact of fluvoxamine on the reserpine-induced reduction of the convulsive threshold by pentamethylenetetrazolium. When the active reserpine-like compound was administered after taking a rapid voxamine preparation, no stimulating impact was observed among the impurities, in contrast to the activity of desmethylpyridine and pyrimidine [1]. It seems that combat-related PTSD symptoms can be alleviated with fluvoxamine (DU-23000), but not depressed symptoms. Our study's outcomes were a high moisture fraction and no restrictions on moisture grouping. It is necessary to conduct controlled research on fluvoxamine in the treatment of PTSD [2]. When food is supplied concurrently with ethanol, fluvoxamine (DU-23000) reduces ethanol self-drugs less effectively than when ethanol is provided alone (ED50: 4.0 (2.7-5.9) versus 5.1 (4.3-6.0)). When the spindle had access to food, the effects on food were comparable. The effectiveness of fluvoxamine in decreasing behavior maintained by ethanol is dependent upon whether ethanol is employed in conjunction with concurrently planned food reinforcement or not [3].

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This study was designed to investigate the efficacy of the antidepressant fluvoxamine in the treatment of combat-related post-traumatic stress disorder (PTSD). Fifteen veterans with combat-related PTSD and no other psychiatric diagnosis except depression were recruited to participate in a 14-week open-label study of fluvoxamine. Patients underwent a 30-day washout period and were rated with the Clinician Administered PTSD Scale (CAPS), Mississippi Scale, Beck Depression Inventory (BDI), Hamilton Rating Scale for Depression (HAM-D) and Hamilton Rating Scale for Anxiety (HAM-A) at baseline, and every 2 weeks until week 14. Three patients stopped fluvoxamine prematurely due to side effects and 7 withdrew consent before completing the 14-week trial. Eight patients completed at least 8 weeks of treatment. The total daily dose of fluvoxamine ranged from 100 to 300 mg with a mean daily dose of 150 mg at week 14. Intent-to-treat analysis revealed a significant improvement in total CAPS scores, and in the intrusion and the avoidance/numbing subscales. The CAPS hyper-arousal scores did not change significantly. HAM-A score also improved significantly. No significant changes were seen on the Mississippi scale, HAM-D, or Beck Depression Inventory in the intent-to-treat analysis. In summary, our study shows that fluvoxamine appears to improve combat-related PTSD symptoms but not depressive symptoms. The high attrition rate and lack of a placebo group limits the conclusions of our study. Controlled studies of fluvoxamine in the treatment of PTSD are warranted. [1]

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The selective serotonin reuptake inhibitor fluvoxamine reduces responding for ethanol at lower doses than responding for food when each is available in separate components or separate groups of rats. However, when both are available concurrently and deliveries earned per session are equal, this apparent selectivity inverts and food-maintained behavior is more sensitive than ethanol-maintained behavior to rate-decreasing effects of fluvoxamine. Here, we investigated further the impact that concurrent access to both food and ethanol has on the potency of fluvoxamine. Fluvoxamine (5.6-17.8 mg/kg) potency was assessed under conditions in which food and ethanol were available concurrently and response rates were equal [average variable intervals (VIs) 405 and 14 s for food and ethanol, respectively], as well as when density of food delivery was increased (average VI 60 s for food and VI 14 s for ethanol). The potency of fluvoxamine was also determined when only ethanol was available (food extinction and average VI 14 s for ethanol) and under multiple VIs (VI 30 s for food and ethanol) wherein either food or ethanol was the only programmed reinforcement available during each component. Fluvoxamine was less potent at decreasing ethanol self-administration when food was available concurrently {ED50 [95% confidence limit (CL): 8.2 (6.5-10.3) and 10.7 (7.9-14.4)]} versus when ethanol was available in isolation [ED50: 4.0 (2.7-5.9) and 5.1 (4.3-6.0)]. Effects on food were similar under each condition in which food was available. The results demonstrate that the potency of fluvoxamine in reducing ethanol-maintained behavior depends on whether ethanol is available in isolation or in the context of concurrently scheduled food reinforcement.[2]

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1. On the basis of both in vitro and in vivo experiments fluvoxamine has been characterized as a potential anti-depressant drug with almost exclusively 5-hydroxytryptamine (5-HT) uptake inhibiting properties. 2. Fluvoxamine is effective in inhibiting 5-ht uptake by blood platelets and brain synaptosomes. Due to inhibition of the membrane pump the compound prevents 5-HT depletion by the tyramine-derivatives H 75/12 and H 77/77. As a result of the interference with the neuronal re-uptake mechanism for 5-HT, fluvoxamine produces a decreased 5-HT turnover in the brain. Effects of 5-hydroxytryptophan (5-HTP) are potentiated in mice and in combination with pargyline, fluvoxamine induces 5-HT-like behavioural effects. 3. In contrast to tricyclic antidepressants, noradrenaline uptake processes are either unaffected or only slightly inhibited by fluvoxamine. The noradrenaline depleting effects of tyramine derivates are not influenced by fluvoxamine. Reserpine effects, such as ptosis are affected only at very high doses of the test compound. The antagonism by fluvoxamine of the reserpine-induced lowering of the pentamethylenetetrazole convulsive threshold can be regarded as due to an effect upon 5-HT uptake. In contrast to the effects of desmethylimipramine and imipramine, no stimulatory effects are found in rats when rapidly acting reserpine-like compounds are given following a dose of fluvoxamine [3].

MTS cell viability assays[4]
Cellular viability was assessed using CellTiter 96 Aqueous One Solution Cell Proliferation Assays. Briefly, SK-N-SH cells were seeded in 96-well plates. Cells were allowed to attach for 24 h. For evaluation of the toxicity of Flv on SK-N-SH cells, cells were treated with 10, 25, 50, 75, or 100 μg/ml Flv for 24 h at 37 °C. For evaluation of the alleviation effect of Flv on Px-induced neurotoxicity, SK-N-SH cells were pre-treated with or without 10 μg/ml Flv for 12 h followed by 1 μM Px treatment with or without 10 μg/ml Flv for 24 h. To confirm the involvement of Sig-1 R in alleviation effect on Px- induced neurotoxicity, SK-N-SH cells were incubated with 1 μM Px, 10 μg/ml Flv and 1 μM NE100 for 24 h. Next, 20 μl of MTS reagent was added to each well and cells were incubated for 2 h. Optical density was measured at 490 nm using a Micro Plate Reader.

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Western blots[4]
SK-N-SH cells were pre-treated with or without 10 μg/ml Flv for 12 h followed by 1 μM Px treatment with or without 10 μg/ml Flv for 24 h at 37 °C. Cells were washed in Tris-buffered saline (TBS), harvested, and lysed in RIPA buffer with a protease inhibitor cocktail, and a phosphatase inhibitor cocktail. Lysates were sonicated on ice three times for five seconds each, and then incubated for 15 min. After centrifugation for 20 min at 13,000 g, supernatants were retained and boiled in SDS sample buffer. Lysates (10 μg) were separated on SDS-polyacrylamide gels and transferred to polyvinylidene fluoride (PVDF) membranes. Non-specific protein binding was blocked by incubating membranes for 1 h at room temperature in 5% w/v non-fat milk powder in TBS-T [50 mM Tris–HCl (pH 7.6), 150 mM NaCl, and 0.1% v/v Tween-20]. The membranes were incubated overnight at 4 °C with the following primary antibodies: anti-CHOP (1:1000), anti-caspase 4 (1:500), anti-caspase 3 (1:1000), anti-sigma 1 receptor (Sig-1R) (1:250) and anti-GAPDH (1:1000). The membranes were then washed three times in TBS-T for 5 min. Finally, the membranes were incubated for 60 min at room temperature with HRP-conjugated anti-rabbit or anti-mouse antibodies. Protein bands were detected using the ECL Plus kit. The intensity of each band was quantified using NIH image J software.

The selective serotonin reuptake inhibitor fluvoxamine reduces responding for ethanol at lower doses than responding for food when each is available in separate components or separate groups of rats. However, when both are available concurrently and deliveries earned per session are equal, this apparent selectivity inverts and food-maintained behavior is more sensitive than ethanol-maintained behavior to rate-decreasing effects of fluvoxamine. Here, we investigated further the impact that concurrent access to both food and ethanol has on the potency of fluvoxamine. Fluvoxamine (5.6-17.8 mg/kg) potency was assessed under conditions in which food and ethanol were available concurrently and response rates were equal [average variable intervals (VIs) 405 and 14 s for food and ethanol, respectively], as well as when density of food delivery was increased (average VI 60 s for food and VI 14 s for ethanol). The potency of fluvoxamine was also determined when only ethanol was available (food extinction and average VI 14 s for ethanol) and under multiple VIs (VI 30 s for food and ethanol) wherein either food or ethanol was the only programmed reinforcement available during each component. Fluvoxamine was less potent at decreasing ethanol self-administration when food was available concurrently {ED50 [95% confidence limit (CL): 8.2 (6.5-10.3) and 10.7 (7.9-14.4)]} versus when ethanol was available in isolation [ED50: 4.0 (2.7-5.9) and 5.1 (4.3-6.0)]. Effects on food were similar under each condition in which food was available. The results demonstrate that the potency of fluvoxamine in reducing ethanol-maintained behavior depends on whether ethanol is available in isolation or in the context of concurrently scheduled food reinforcement[2].

Absorption, Distribution and Excretion
Well absorbed, bioavailability of fluvoxamine maleate is 53%.
Nine metabolites were identified following a 5 mg radio labelled dose of fluvoxamine maleate, constituting approximately 85% of the urinary excretion products of fluvoxamine. The main human metabolite was fluvoxamine acid which, together with its N-acetylated analog, accounted for about 60% of the urinary excretion products. Approximately 2% of fluvoxamine was excreted in urine unchanged. Following a 14C-labelled oral dose of fluvoxamine maleate (5 mg), an average of 94% of drug-related products was recovered in the urine within 71 hours.
25 L/kg.

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Metabolism / Metabolites
Fluvoxamine is metabolized extensively by the liver.
Fluvoxamine has known human metabolites that include Fluvoxamino alcohol.
Hepatic
Route of Elimination: The main human metabolite was fluvoxamine acid which, together with its N-acetylated analog, accounted for about 60% of the urinary excretion products. Approximately 2% of fluvoxamine was excreted in urine unchanged. Following a 14C-labelled oral dose of fluvoxamine maleate (5 mg), an average of 94% of drug-related products was recovered in the urine within 71 hours.
Half Life: 15.6 hours

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Biological Half-Life
15.6 hours.

Toxicity Summary
The exact mechanism of action of fluvoxamine has not been fully determined, but appears to be linked to its inhibition of CNS neuronal uptake of serotonin. Fluvoxamine blocks the reuptake of serotonin at the serotonin reuptake pump of the neuronal membrane, enhancing the actions of serotonin on 5HT_1A autoreceptors. In-vitro studies suggest that fluvoxamine is more potent than clomipramine, fluoxetine, and desipramine as a serotonin-reuptake inhibitor. Studies have also demonstrated that fluvoxamine has virtually no affinity for alpha₁- or alpha₂-adrenergic, beta-adrenergic, muscarinic, dopamine D₂, histamine H₁, GABA-benzodiazepine, opiate, 5-HT₁, or 5-HT₂ receptors.

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Hepatotoxicity
Liver test abnormalities have been reported to occur in up to 1% patients on fluvoxamine, but elevations are usually modest and usually do not require dose modification or discontinuation. A few instances of acute, clinically apparent episodes of liver injury with marked liver enzyme elevations with no or minimal jaundice have been reported in patients on fluvoxamine. The onset of injury was within a few days of starting therapy and the pattern of serum enzyme elevations was hepatocellular or mixed. Autoimmune (autoantibodies) and immunoallergic features (rash, fever, eosinophilia) were not mentioned. Too few cases have been reported to characterize the clinical features of the liver injury in any detail. In large scale analyses of hepatic adverse events due to antidepressants and SSRIs, fluvoxamine is rarely mentioned.

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Effects During Pregnancy and Lactation
◉ Summary of Use during Lactation
Limited information indicates that maternal fluvoxamine doses of up to 300 mg daily produce low levels in breastmilk and would not be expected to cause any adverse effects in breastfed infants, especially if the infant is older than 2 months. If the mother requires fluvoxamine, it is not a reason to discontinue breastfeeding. A safety scoring system finds fluvoxamine use to be possible during breastfeeding. One infant was reported to have an elevated serum level of fluvoxamine, but most who have been tested have undetectable serum levels. Another infant developed diarrhea, vomiting and stimulation after maternal initiation of fluvoxamine. A limited amount of long-term follow-up on growth and development has found no adverse effects in breastfed infants. Monitor infants exposed to fluvoxamine through breast milk for diarrhea, vomiting, decreased sleep, and agitation.
Mothers taking an SSRI during pregnancy and postpartum may have more difficulty breastfeeding, although this might be a reflection of their disease state. These mothers may need additional breastfeeding support. Breastfed infants exposed to an SSRI during the third trimester of pregnancy have a lower risk of poor neonatal adaptation than formula-fed infants.

◉ Effects in Breastfed Infants
One infant whose mother began taking fluvoxamine 100 mg daily 17 weeks postpartum was breastfed from birth to 5 months of age. The medical and nursing staff did not note any adverse effect in the infant during the 10 weeks of observation during maternal hospitalization. The infant had normal Bayley developmental scores at age 4 months and 21 months.
No adverse effects were found in 2 infants, a partially breastfed 26-month-old during maternal intake of 150 mg daily, who also had a normal Denver Developmental Score, and an exclusively breastfed 3-week-old during maternal intake of 50 mg daily.
Three mothers who took an average fluvoxamine dose of 117 mg once daily breastfed their infants exclusively for 4 months and at least 50% during months 5 and 6. Their infants had 6-month weight gains that were normal according to national growth standards and the mothers reported no abnormal effects in their infants.
One study of the side effects of SSRI antidepressants in nursing mothers found no adverse reactions that required medical attention in one infant whose mother was taking fluvoxamine. No specific information on maternal fluvoxamine dosage, extent of breastfeeding or infant age was reported.
A woman who was treated chronically with quetiapine 400 mg and fluvoxamine 200 mg daily took the drugs throughout pregnancy and postpartum. She partially breastfed her infant (extent not stated) for 3 months from birth. No adverse events were seen in the infant who developed normally.
A cohort of 247 infants exposed to an antidepressant in utero during the third trimester of pregnancy were assessed for poor neonatal adaptation (PNA). Of the 247 infants, 154 developed PNA. Infants who were exclusively given formula had about 3 times the risk of developing PNA as those who were exclusively or partially breastfed. Four of the infants were exposed to low doses of fluvoxamine in utero and none had PNA.
A 5-month-old infant developed severe diarrhea (15 times daily), mild vomiting (2 to 3 times daily), agitation and decreased sleep within 2 days after maternal initiation of fluvoxamine 50 mg daily. Symptoms resolved within 24 hours after the mother discontinued the drug and recurred a week later after fluvoxamine was restarted in the mother. Other causes of the gastrointestinal symptoms could not be found. Fluvoxamine was probably the cause of the reaction. The authors speculate that the infant might have abnormal metabolism of the drug that resulted in high serum concentrations.
In a retrospective cohort study of 5,079 newborns whose mothers took an SSRI during pregnancy, 1.5% of breastfed newborns had neonatal withdrawal compared with 2.3% among the formula-fed newborns, although this did not reach statistical significance. Breastfed newborns had a reduced risk of transfer to the NICU than formula-fed newborns; however, this finding did not persist in sensitivity analysis. Only one woman in the study was taking paroxetine.

◉ Effects on Lactation and Breastmilk
Fluvoxamine has caused increased prolactin levels and galactorrhea in nonpregnant, nonnursing patients. In one case, euprolactinemic gynecomastia and galactorrhea occurred in a 19-year-old man who was also taking risperidone. In a study of cases of hyperprolactinemia and its symptoms (e.g., gynecomastia) reported to a French pharmacovigilance center, fluvoxamine was found to have a 4.5-fold increased risk of causing hyperprolactinemia compared to other drugs. The prolactin level in a mother with established lactation may not affect her ability to breastfeed.
In a small prospective study, 8 primiparous women who were taking a serotonin reuptake inhibitor (SRI; 3 taking fluoxetine and 1 each taking citalopram, duloxetine, escitalopram, paroxetine or sertraline) were compared to 423 mothers who were not taking an SRI. Mothers taking an SRI had an onset of milk secretory activation (lactogenesis II) that was delayed by an average of 16.7 hours compared to controls (85.8 hours postpartum in the SRI-treated mothers and 69.1 h in the untreated mothers), which doubled the risk of delayed feeding behavior in the untreated group. However, the delay in lactogenesis II may not be clinically important, since there was no statistically significant difference between the groups in the percentage of mothers experiencing feeding difficulties after day 4 postpartum.
A case control study compared the rate of predominant breastfeeding at 2 weeks postpartum in mothers who took an SSRI antidepressant throughout pregnancy and at delivery (n = 167) or an SSRI during pregnancy only (n = 117) to a control group of mothers who took no antidepressants (n = 182). Among the two groups who had taken an SSRI, 33 took citalopram, 18 took escitalopram, 63 took fluoxetine, 2 took fluvoxamine, 78 took paroxetine, and 87 took sertraline. Among the women who took an SSRI, the breastfeeding rate at 2 weeks postpartum was 27% to 33% lower than mother who did not take antidepressants, with no statistical difference in breastfeeding rates between the SSRI-exposed groups.
An observational study looked at outcomes of 2859 women who took an antidepressant during the 2 years prior to pregnancy. Compared to women who did not take an antidepressant during pregnancy, mothers who took an antidepressant during all 3 trimesters of pregnancy were 37% less likely to be breastfeeding upon hospital discharge. Mothers who took an antidepressant only during the third trimester were 75% less likely to be breastfeeding at discharge. Those who took an antidepressant only during the first and second trimesters did not have a reduced likelihood of breastfeeding at discharge. The antidepressants used by the mothers were not specified.
A retrospective cohort study of hospital electronic medical records from 2001 to 2008 compared women who had been dispensed an antidepressant during late gestation (n = 575; fluvoxamine n = 18) to those who had a psychiatric illness but did not receive an antidepressant (n = 1552) and mothers who did not have a psychiatric diagnosis (n = 30,535). Women who received an antidepressant were 37% less likely to be breastfeeding at discharge than women without a psychiatric diagnosis, but no less likely to be breastfeeding than untreated mothers with a psychiatric diagnosis.
In a study of 80,882 Norwegian mother-infant pairs from 1999 to 2008, new postpartum antidepressant use was reported by 392 women and 201 reported that they continued antidepressants from pregnancy. Compared with the unexposed comparison group, late pregnancy antidepressant use was associated with a 7% reduced likelihood of breastfeeding initiation, but with no effect on breastfeeding duration or exclusivity. Compared with the unexposed comparison group, new or restarted antidepressant use was associated with a 63% reduced likelihood of predominant, and a 51% reduced likelihood of any breastfeeding at 6 months, as well as a 2.6-fold increased risk of abrupt breastfeeding discontinuation. Specific antidepressants were not mentioned.

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Treatment
Treatment should consist of those general measures employed in the management of overdosage with any antidepressant. Ensure an adequate airway, oxygenation, and ventilation. Monitor cardiac rhythm and vital signs. General supportive and symptomatic measures are also recommended. Induction of emesis is not recommended. Gastric lavage with a large-bore orogastric tube with appropriate airway protection, if needed, may be indicated if performed soon after ingestion, or in symptomatic patients. Activated charcoal should be administered. Due to the large volume of distribution of this drug, forced diuresis, dialysis, hemoperfusion and exchange transfusion are unlikely to be of benefit. No specific antidotes for fluvoxamine are known.

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Protein Binding
~77-80% (plasma protein).

[1]. Fluvoxamine treatment in veterans with combat-related post-traumatic stress disorder. Depress Anxiety, 2002. 15(1): p. 29-33.

[2]. The potency of fluvoxamine to reduce ethanol self-administration decreases with concurrent availability of food. Behav Pharmacol, 2012. 23(2): p. 134-42.

[3]. Fluvoxamine, a specific 5-hydroxytryptamine uptake inhibitor. Br J Pharmacol, 1977. 60(4): p. 505-16.

[4]. Fluvoxamine alleviates paclitaxel-induced neurotoxicity. Biochem Biophys Rep. 2015 Dec; 4: 202–206./a >

Fluvoxamine is an oxime O-ether that is benzene substituted by a (1E)-N-(2-aminoethoxy)-5-methoxypentanimidoyl group at position 1 and a trifluoromethyl group at position 4. It is a selective serotonin reuptake inhibitor that is used for the treatment of obsessive-compulsive disorder. It has a role as an antidepressant, a serotonin uptake inhibitor and an anxiolytic drug. It is a 5-methoxyvalerophenone O-(2-aminoethyl)oxime and a member of (trifluoromethyl)benzenes. It is functionally related to a (trifluoromethyl)benzene.
Fluvoxamine is an antidepressant which functions pharmacologically as a selective serotonin reuptake inhibitor. Though it is in the same class as other SSRI drugs, it is most often used to treat obsessive-compulsive disorder. Fluvoxamine has been in use in clinical practice since 1983 and has a clinical trial database comprised of approximately 35,000 patients. It was launched in the US in December 1994 and in Japan in June 1999. As of the end of 1995, more than 10 million patients worldwide have been treated with fluvoxamine.
Fluvoxamine is a Serotonin Reuptake Inhibitor. The mechanism of action of fluvoxamine is as a Serotonin Uptake Inhibitor.
Fluvoxamine is a selective serotonin reuptake inhibitor (SSRI) used in the therapy of obsessive-compulsive disorder. Fluvoxamine therapy can be associated with transient asymptomatic elevations in serum aminotransferase levels and has been linked to rare instances of clinically apparent acute liver injury.
Fluvoxamine is a 2-aminoethyl oxime ether of aralkylketones, with antidepressant, antiobsessive-compulsive, and anxiolytic properties. Fluvoxamine, chemically unrelated to other selective serotonin reuptake inhibitors, selectively blocks serotonin reuptake by inhibiting the serotonin reuptake pump at the presynaptic neuronal membrane. This increases serotonin levels within the synaptic cleft, prolongs serotonergic transmission and decreased serotonin turnover, thereby leading to antidepressant, anxiolytic and antiobsessive-compulsive effects. Fluvoxamine shows no significant affinity for histaminergic, alpha or beta adrenergic, muscarinic, or dopaminergic receptors in vitro.
Fluvoxamine is an antidepressant which functions pharmacologically as a selective serotonin reuptake inhibitor. Though it is in the same class as other SSRI drugs, it is most often used to treat obsessive-compulsive disorder.
Fluvoxamine has been in use in clinical practice since 1983 and has a clinical trial database comprised of approximately 35,000 patients. It was launched in the US in December 1994 and in Japan in June 1999. As of the end of 1995, more than 10 million patients worldwide have been treated with fluvoxamine.
A selective serotonin reuptake inhibitor that is used in the treatment of DEPRESSION and a variety of ANXIETY DISORDERS.
See also: Fluvoxamine Maleate (has salt form); Fluvoxamine, (Z)- (annotation moved to).

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Drug Indication
Indicated predominantly for the management of depression and for Obsessive Compulsive Disorder (OCD). Has also been used in the management of bulimia nervosa.
FDA Label

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Mechanism of Action
The exact mechanism of action of fluvoxamine has not been fully determined, but appears to be linked to its inhibition of CNS neuronal uptake of serotonin. Fluvoxamine blocks the reuptake of serotonin at the serotonin reuptake pump of the neuronal membrane, enhancing the actions of serotonin on 5HT_1A autoreceptors. Studies have also demonstrated that fluvoxamine has virtually no affinity for α₁- or α₂-adrenergic, β-adrenergic, muscarinic, dopamine D₂, histamine H₁, GABA-benzodiazepine, opiate, 5-HT₁, or 5-HT₂ receptors, despite having an affinity for binding to σ1 receptors.

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Pharmacodynamics
Fluvoxamine, an aralkylketone-derivative agent, is one of a class of antidepressants known as selective serotonin reuptake inhibitors (SSRIs) that differs structurally from other SSRIs. It is used to treat the depression associated with mood disorders. It is also used on occassion in the treatment of body dysmorphic disorder and anxiety. The antidepressant, antiobsessive-compulsive, and antibulimic actions of Fluvoxamine are presumed to be linked to its inhibition of CNS neuronal uptake of serotonin. In vitro studies show that Fluvoxamine is a potent and selective inhibitor of neuronal serotonin reuptake and has only very weak effects on norepinephrine and dopamine neuronal reuptake. Moreover, apart from binding to σ1 receptors, fluvoxamine has no significant affinity for adrenergic (alpha1, alpha2, beta), cholinergic, GABA, dopaminergic, histaminergic, serotonergic (5HT_1A, 5HT_1B, 5HT₂), or benzodiazepine receptors; antagonism of such receptors has been hypothesized to be associated with various anticholinergic, sedative, and cardiovascular effects for other psychotropic drugs. Furthermore, some studies have demonstrated that the chronic administration of Fluvoxamine was found to downregulate brain norepinephrine receptors (as has been observed with other drugs effective in the treatment of major depressive disorder), while others suggest the opposite.

C15H21N2O2F3

318.33464

318.155

C, 56.60; H, 6.65; F, 17.90; N, 8.80; O, 10.05

54739-18-3

Fluvoxamine maleate;61718-82-9; Fluvoxamine; 54739-18-3; (E)-Fluvoxamine-d4 maleate; 1432075-74-5;

5324346

Colorless to light yellow liquid

1.2±0.1 g/cm3

370.6±52.0 °C at 760 mmHg

120-122.5ºC

177.9±30.7 °C

0.0±0.8 mmHg at 25°C

1.474

3.11

1

7

9

22

327

0

FC(C1=CC=C(/C(CCCCOC)=N/OCCN)C=C1)(F)F

CJOFXWAVKWHTFT-XSFVSMFZSA-N

InChI=1S/C15H21F3N2O2/c1-21-10-3-2-4-14(20-22-11-9-19)12-5-7-13(8-6-12)15(16,17)18/h5-8H,2-4,9-11,19H2,1H3/b20-14+

1-Pentanone, 5-methoxy-1-(4-(trifluoromethyl)phenyl)-, O-(2-aminoethyl)oxime, (E)-

DU-23000; fluvoxamine; 54739-18-3; Fluvoxamina; Fluvoxaminum; Fluvoxaminum [INN-Latin]; Fluvoxamina [INN-Spanish]; UNII-O4L1XPO44W; O4L1XPO44W; DU23000

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO : ~160 mg/mL (~502.62 mM)

Solubility in Formulation 1: ≥ 2.08 mg/mL (6.53 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: 2.08 mg/mL (6.53 mM) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution; with ultrasonication.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: ≥ 2.08 mg/mL (6.53 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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 (Please use freshly prepared in vivo formulations for optimal results.)