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
Fluvoxamine maleate is well absorbed, with a bioavailability of 53%. Following administration of 5 mg of radiolabeled fluvoxamine maleate, nine metabolites were identified, accounting for approximately 85% of fluvoxamine excretion in urine. The major human metabolite is fluvoxamine acid, which, along with its N-acetylated analogues, accounts for approximately 60% of urinary excretion. Approximately 2% of fluvoxamine is excreted unchanged in urine. Following oral administration of 5 mg of 14C-labeled fluvoxamine maleate, an average of 94% of drug-related products are recovered from urine within 71 hours. 25 L/kg.hr Metabolism/Metabolites Fluvoxamine is primarily metabolized in the liver. Known human metabolites of fluvoxamine include fluvoxamine amino alcohol.
Hepatic Excretion Route: The main human metabolite is fluvoxamine acid, which and its N-acetylated analogs account for approximately 60% of urinary excretion. Approximately 2% of fluvoxamine is excreted unchanged in the urine. Following oral administration of 14C-labeled fluvoxamine maleate (5 mg), an average of 94% of drug-related products were 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 is not fully understood, but it appears to be related to its inhibition of serotonin uptake by neurons in the central nervous system. Fluvoxamine blocks the reuptake of serotonin by the serotonin reuptake pump on the neuronal membrane, thereby enhancing the effect of serotonin on its 5-hydroxytryptamine 1A autoreceptor. In vitro studies have shown that fluvoxamine, as a serotonin reuptake inhibitor, is more potent than clomipramine, fluoxetine, and desipramine. Studies have also shown that fluvoxamine has almost no affinity for α1- or α2-adrenergic receptors, β-adrenergic receptors, muscarinic receptors, dopamine D2 receptors, histamine H1 receptors, GABA-benzodiazepine receptors, opioid receptors, 5-HT1 receptors, or 5-HT2 receptors. Hepatotoxicity
Up to 1% of patients taking fluvoxamine have been reported to experience abnormal liver function, but the elevation is usually small and generally does not require dose adjustment or discontinuation. A small number of patients taking fluvoxamine have reported acute, clinically significant liver injury with markedly elevated liver enzymes, but without or with only mild jaundice. The injury typically occurs within days of starting treatment, with serum enzyme elevations presenting as hepatocellular or mixed. Autoimmune (autoantibodies) and immune hypersensitivity features (rash, fever, eosinophilia) are not mentioned. The number of reported cases is too small to provide a detailed description of the clinical features of liver injury. Fluvoxamine is rarely mentioned in large-scale analyses of adverse liver events associated with antidepressants and selective serotonin reuptake inhibitors (SSRIs).

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Effects during pregnancy and lactation
◉ Overview of use during lactation
Limited information suggests that daily administration of fluvoxamine up to 300 mg results in low concentrations in breast milk and is not expected to have any adverse effects on breastfed infants, especially those older than 2 months. If a mother needs to take fluvoxamine, this is not a reason to discontinue breastfeeding. A safety rating system considers fluvoxamine safe for use during lactation. One case reported elevated serum fluvoxamine levels in an infant, but fluvoxamine levels were undetectable in the serum of most infants tested. Another infant experienced diarrhea, vomiting, and agitation after their mother began taking fluvoxamine. Limited long-term growth and development follow-up studies found no adverse reactions in breastfed infants. Infants exposed to fluvoxamine through breast milk should be monitored for symptoms such as diarrhea, vomiting, decreased sleep, and restlessness. Mothers taking selective serotonin reuptake inhibitors (SSRIs) during pregnancy and postpartum may find breastfeeding more difficult, but this may reflect their disease state. These mothers may require additional breastfeeding support. Breastfed infants exposed to SSRIs in late pregnancy have a lower risk of neonatal maladaptive disorder than formula-fed infants. ◉ Effects on Breastfed Infants
One mother started taking 100 mg of fluvoxamine daily at 17 weeks postpartum, and the infant was breastfed from birth until 5 months of age. During the 10-week observation period while the mother was hospitalized, no adverse reactions were observed in the infant. The infant's Bayley Developmental Schedules scores were normal at 4 months and 21 months of age. Two other infants also showed no adverse reactions: a 26-month-old infant whose mother took 150 mg of fluvoxamine daily and was partially breastfed, also had a normal Denver Developmental Schedules score; another 3-week-old infant whose mother took 50 mg of fluvoxamine daily and was exclusively breastfed. The three mothers took an average of 117 mg of fluvoxamine daily, exclusively breastfed their infants for 4 months, and breastfed at least 50% of their babies in the 5th and 6th months. These infants' weight gain at 6 months met national growth standards, and the mothers did not report any adverse reactions in their infants. A study on the side effects of selective serotonin reuptake inhibitors (SSRIs) in breastfeeding mothers found that an infant born to a mother taking fluvoxamine did not experience any adverse reactions requiring medical attention. Specific information regarding maternal fluvoxamine dosage, breastfeeding extent, or infant age was not reported. A woman who had been taking quetiapine 400 mg and fluvoxamine 200 mg long-term throughout her pregnancy and postpartum took these medications. She partially breastfed her infant for 3 months from birth (expansion unspecified). The infant developed normally without any adverse events. A cohort study of 247 infants exposed to antidepressants in utero during late pregnancy assessed neonatal maladaptive disorder (PNA). Of these 247 infants, 154 developed PNA. The risk of PNA was approximately three times higher in exclusively formula-fed infants than in exclusively or partially breastfed infants. Four infants were exposed to low doses of fluvoxamine in utero but did not develop postpartum neuropathic pain. A 5-month-old infant developed severe diarrhea (15 times daily), mild vomiting (2 to 3 times daily), irritability, and reduced sleep two days after her mother began taking fluvoxamine (50 mg daily). The mother's symptoms disappeared 24 hours after stopping the medication; a week later, the symptoms recurred when the mother took fluvoxamine again. No other causes of gastrointestinal symptoms were found. Fluvoxamine is likely the cause of the reaction. The authors speculate that the infant may have a drug metabolism disorder leading to excessively high serum drug concentrations. A retrospective cohort study included 5079 newborns whose mothers had taken selective serotonin reuptake inhibitors (SSRIs) during pregnancy. The results showed that 1.5% of breastfed newborns experienced neonatal withdrawal symptoms, compared to 2.3% of formula-fed newborns, but the difference was not statistically significant. Breastfed newborns had a lower risk of being transferred to the neonatal intensive care unit (NICU) than formula-fed newborns; however, sensitivity analysis did not confirm this result. Only one woman in this study took paroxetine. Effects on lactation and breast milk: Fluvoxamine can cause elevated prolactin levels and galactorrhea in non-pregnant, non-lactating patients. In one case, a 19-year-old male experienced normal prolactinemia-induced gynecomastia and galactorrhea while taking risperidone. A study of cases of hyperprolactinemia and its symptoms (such as gynecomastia) reported by the French National Center for Pharmacovigilance found that fluvoxamine increased the risk of hyperprolactinemia by 4.5 times compared to other medications. Prolactin levels in established lactating mothers may not affect their ability to breastfeed. In a small prospective study, researchers compared eight primiparous women taking serotonin reuptake inhibitors (SRIs; three took fluoxetine, and the remaining one took citalopram, duloxetine, escitalopram, paroxetine, or sertraline, respectively) with 423 mothers not taking SRIs. Mothers taking selective serotonin reuptake inhibitors (SSRIs) experienced a mean delay of 16.7 hours initiation of lactation activation (stage II) compared to the control group (85.8 hours postpartum in the SSRI treatment group vs. 69.1 hours postpartum in the untreated group), which doubled the risk of delayed feeding behavior in the untreated group. However, the delay in stage II lactation may not be clinically significant, as there was no statistically significant difference between the two groups in the proportion of mothers experiencing feeding difficulties after day 4 postpartum. A case-control study compared breastfeeding rates at 2 weeks postpartum in mothers who took SSRIs throughout pregnancy and delivery (n = 167), mothers who took SSRIs only during pregnancy (n = 117), and control mothers who did not take antidepressants (n = 182). In two groups of participants who took selective serotonin reuptake inhibitors (SSRIs), 33 took citalopram, 18 took escitalopram, 63 took fluoxetine, 2 took fluvoxamine, 78 took paroxetine, and 87 took sertraline. Among women taking SSRIs, the breastfeeding rate at two weeks postpartum was 27% to 33% lower than that of mothers not taking antidepressants, but there was no statistically significant difference in breastfeeding rates between the SSRI exposure groups. An observational study investigated the outcomes of 2,859 women who had taken antidepressants in the two years prior to pregnancy. Compared to women who did not take antidepressants during pregnancy, mothers who took antidepressants in all three stages of pregnancy were 37% less likely to breastfeed at discharge. Mothers who took antidepressants only in the third trimester were 75% less likely to breastfeed at discharge. Pregnant women who took antidepressants only in the first and second trimesters were not less likely to breastfeed at discharge. However, the study did not specify the type of antidepressant used by the mothers. A retrospective cohort study analyzed hospital electronic medical records from 2001 to 2008, comparing women taking antidepressants in late pregnancy (n = 575; of whom n = 18 took fluvoxamine), women with mental illness but not taking antidepressants (n = 1552), and mothers not diagnosed with mental illness (n = 30,535). Women receiving antidepressant treatment were 37% less likely to breastfeed at discharge than women not diagnosed with mental illness, but there was no difference in the likelihood of breastfeeding compared to untreated mothers diagnosed with mental illness. A Norwegian study of 80,882 mother-infant pairs from 1999 to 2008 showed that 392 women reported starting antidepressants postpartum, and 201 women reported starting antidepressants during pregnancy. Compared to a control group not exposed to antidepressants, taking antidepressants in late pregnancy was associated with a 7% lower likelihood of initiating breastfeeding, but had no effect on the duration of breastfeeding or the rate of exclusive breastfeeding. Compared to the control group who had not been exposed to antidepressants, recent use or restart of antidepressants was associated with a 63% lower likelihood of primary breastfeeding at 6 months, a 51% lower likelihood of any breastfeeding, and a 2.6-fold increased risk of abrupt cessation of breastfeeding. No specific antidepressant was mentioned. Treatment: Treatment should include general measures for any antidepressant overdose. Ensure a patent airway, oxygenation, and ventilation. Monitor heart rhythm and vital signs. General supportive and symptomatic treatment is recommended. Induction of vomiting is not recommended. If necessary, gastric lavage may be performed shortly after administration or in symptomatic patients using a large-bore gastric tube, with appropriate airway protection. Activated charcoal should be administered. Due to the high distribution of this drug, forced diuresis, dialysis, hemoperfusion, and exchange transfusion may be ineffective. There is currently no specific antidote for fluvoxamine. Protein binding: ~77-80% (plasma proteins).

[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 ether with a benzene ring structure, substituted at position 1 with (1E)-N-(2-aminoethoxy)-5-methoxypentanimide and position 4 with a trifluoromethyl group. It is a selective serotonin reuptake inhibitor (SSRI) used to treat obsessive-compulsive disorder (OCD). It has antidepressant, serotonin reuptake inhibitor, and anxiolytic effects. It is a 5-methoxypentanone O-(2-aminoethyl)oxime, belonging to the (trifluoromethyl)benzene class of compounds. Its function is similar to (trifluoromethyl)benzene. Fluvoxamine is an antidepressant whose mechanism of action is as a selective serotonin reuptake inhibitor. Although it belongs to the same class as other SSRIs, it is most commonly used to treat OCD. Fluvoxamine has been used clinically since 1983, and its clinical trial database contains data from approximately 35,000 patients. It was launched in the United States in December 1994 and in Japan in June 1999. By the end of 1995, over 10 million patients worldwide had received fluvoxamine treatment. Fluvoxamine is a serotonin reuptake inhibitor (SSRI). Its mechanism of action is the inhibition of serotonin reuptake. Fluvoxamine is a selective serotonin reuptake inhibitor (SSRI) used to treat obsessive-compulsive disorder (OCD). Fluvoxamine treatment may cause a transient, asymptomatic increase in serum transaminase levels, and has been reported in rare cases of clinically significant acute liver injury. Fluvoxamine is a 2-aminoethyl oxime ether of an aralkyl ketone with antidepressant, anti-obsessive-compulsive, and anti-anxiety effects. Fluvoxamine is chemically independent of other SSRIs; it selectively blocks the reuptake of serotonin by inhibiting the serotonin reuptake pump on the presynaptic neuronal membrane. This increases serotonin levels in the synaptic cleft, prolongs serotonergic neurotransmission time, and reduces serotonin metabolic turnover, thereby producing antidepressant, anti-anxiety, and anti-obsessive-compulsive effects. In vitro experiments have shown that fluvoxamine has no significant affinity for histamine receptors, α or β adrenergic receptors, muscarinic receptors, or dopaminergic receptors. Fluvoxamine is an antidepressant whose pharmacological mechanism of action is selective serotonin reuptake inhibitor (SSRI). Although it belongs to the same class of SSRIs as other drugs, it is most commonly used to treat obsessive-compulsive disorder. Fluvoxamine has been used clinically since 1983, and its clinical trial database contains data from approximately 35,000 patients. The drug was launched in the United States in December 1994 and in Japan in June 1999. By the end of 1995, more than 10 million patients worldwide had received fluvoxamine treatment.
Fluvoxamine is a selective serotonin reuptake inhibitor used to treat depression and various anxiety disorders.
See also: Fluvoxamine maleate (in salt form); (Z)-Fluvoxamine (note moved here).
Indications
Primarily used to treat depression and obsessive-compulsive disorder (OCD). Also previously used to treat bulimia nervosa.
FDA label

Mechanism of Action
The exact mechanism of action of fluvoxamine is not fully understood, but it appears to be related to its inhibition of serotonin reuptake by neurons in the central nervous system. Fluvoxamine blocks the reuptake of serotonin by the serotonin reuptake pump on the neuronal membrane, enhancing the effect of serotonin on its own receptor 5HT1A. Studies have also shown that although fluvoxamine has a binding affinity for σ1 receptors, it has almost no affinity for α1 or α2 adrenergic receptors, β-adrenergic receptors, muscarinic receptors, dopamine D2 receptors, histamine H1 receptors, GABA-benzodiazepine receptors, opioid receptors, 5-HT1 receptors, or 5-HT2 receptors.

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Pharmacodynamics
Fluvoxamine is an aryl ketone derivative, belonging to the class of selective serotonin reuptake inhibitors (SSRIs) antidepressants, and its structure differs from other SSRIs. It is used to treat depression associated with mood disorders. It is sometimes also used to treat body dysmorphic disorder and anxiety disorders. The antidepressant, anti-obsessive-compulsive, and anti-bulimia effects of fluvoxamine are thought to be related to its inhibition of serotonin reuptake by neurons in the central nervous system. In vitro studies have shown that fluvoxamine is a potent and selective inhibitor of neuronal serotonin reuptake, with only very weak effects on neuronal reuptake of norepinephrine and dopamine. In addition to binding to σ1 receptors, fluvoxamine has no significant affinity for adrenergic (α1, α2, β), cholinergic, GABA, dopaminergic, histaminergic, serotonergic (5HT1A, 5HT1B, 5HT2), or benzodiazepine receptors. Some studies hypothesize that the antagonistic effects of these receptors are related to the anticholinergic, sedative, and cardiovascular effects of certain psychotropic drugs. Furthermore, some studies have shown that long-term use of fluvoxamine downregulates norepinephrine receptors in the brain (consistent with observations of other effective drugs for treating major depressive disorder), while other studies 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.)