SSRIs/selective serotonin reuptake inhibitors

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.

Fluvoxamine maleate likewise demonstrates dose-dependent antinociception in the paw pressure test in non-ligated mice. In the acute paw pressure test, fluoxetine maleate also produces an antinociceptive effect that is countered by granisetron, an antagonist of the 5-HT3 receptor.[2] Fluvoxamine (10 and 30 mg/kg, i.p.) dose-dependently increases synaptic efficacy in the hippocampo-mPFC pathway in the rat hippocampo-medial prefrontal cortex (mPFC).[3] In rats under anesthesia, fluvoxamine (10 and 30 mg/kg, i.p.) inhibits long-term potentiation (LTP) in the hippocampal CA1 field. While the 5-HT(4) receptor antagonist GR 113808 (20 mg/rat, i.c.v.) and the 5-HT(7) receptor antagonist DR 4004 (10 mg/rat, i.c.v.) do not completely reverse the suppression of LTP induced by fluvoxamine (30 mg/kg, i.p.), they do.[4] An isolated rat vas deferens cultured in Krebs-Henseleit solution responds to norepinephrine more strongly when fluvoxamine maleate is added. With an IC50 of 18.2μM and 3.99μM, respectively, fluoxetine hydrochloride and fluoxetine maleate inhibit the contraction brought on by potassium ions in the isolated rat uterus preparation.

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Quetiapine had no significant effect on [DA]ex and [5-HT]ex levels in the prefrontal cortex and thalamus, but increased [DA]ex and [5-HT]ex levels in the dorsal striatum. In the accumbens, quetiapine increased [DA]ex levels and decreased [5-HT]ex levels. Fluvoxamine increased [5-HT]ex levels in all brain areas, and also increased [DA]ex levels in the striatum. The combination of quetiapine with fluvoxamine increased [DA]ex and [5-HT]ex levels in all brain areas compared with baseline. Although neither quetiapine nor fluvoxamine in monotherapy affected [DA]ex levels in the prefrontal cortex and thalamus, the combination produced a significant increase of [DA]ex levels in these two brain areas.[1]

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There is an association between depression and chronic pain, and some antidepressants exert antinociceptive effects in humans and laboratory animals. We examined the effects of Fluvoxamine, a selective serotonin reuptake inhibitor, on mechanical allodynia and its mechanism of action in the mouse chronic pain model, which was prepared by partially ligating the sciatic nerve. The antiallodynic effect was measured using the von Frey test. Fluvoxamine produced antiallodynic effects following both systemic and intrathecal administration. In 5-hydroxytryptamine (5-HT)-depleted mice, prepared by intracerebroventricular injection of 5,7-dihyroxytryptamine, the fluvoxamine-induced antiallodynic effect was significantly attenuated. The antiallodynic effects of systemic fluvoxamine were also reduced by both systemic and intrathecal administration of ketanserin, a 5-HT2A/2C receptor antagonist. In addition, fluvoxamine also induced antinociceptive effect in the acute paw pressure test, and this effect was antagonized by the 5-HT3 receptor antagonist granisetron. These results indicate that fluvoxamine exerts its antiallodynic effects on neuropathic pain via descending 5-HT fibers and spinal 5-HT2A or 5-HT2C receptors, and the antinociception on acute mechanical pain via 5-HT3 receptors. [2]

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The present studies were conducted to examine the effects of single and repeated treatments with Fluvoxamine, which is a selective serotonin reuptake inhibitor (SSRI), on the synaptic efficacy and synaptic plasticity in the rat hippocampo-medial prefrontal cortex (mPFC) pathway in vivo. It has been reported that the projections arising from the hippocampal structures to the mPFC are involved in the execution of higher cognitive functions in rats. The evoked potentials were recorded in the mPFC by stimulation of the CA1/subicular region of the ventral hippocampus in halothane-anesthetized rats. Single administration of fluvoxamine (10 and 30 mg/kg, i.p.) enhanced synaptic efficacy in the hippocampo-mPFC pathway in a dose-dependent manner. Although repeated treatments with fluvoxamine (30 mg/kg, i.p. after 30 mg/kg/day×21 days, p.o.) caused an enhancement of synaptic efficacy, there was no significant difference between single and repeated treatments. The input/output characteristics showed hypersensitivity to stimulation intensity in the group with repeated fluvoxamine treatments. The establishment of long-term potentiation (LTP) in the hippocampo-mPFC pathway after a single administration of fluvoxamine was not different from that in the saline-injected group. On the other hand, the hippocampo-mPFC LTP was significantly augmented by repeated treatments with fluvoxamine when compared to a single treatment. These findings suggest that the serotonergic system could modulate the synaptic plasticity at hippocampal-mPFC synapses. The present study, furthermore, suggests that the enhancement of LTP in the hippocampo-mPFC pathway produced by repeated treatments with fluvoxamine may be implicated in the SSRI-induced therapeutic effect on psychiatric disorders[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 (Roche, Mannheim, Germany), 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.

Fluvoxamine maleate, amitriptyline hydrochloride, WAY100635 maleate and ketanserin tartrate were dissolved in 0.9% saline. When given i.p. or subcutaneously (s.c.), the drugs were administered in a volume of 0.1 ml/10 g body weight. For intrathecal (i.t.) injection, the drugs were administered in a volume of 5 μl via a disposable 27-gauge needle, which was inserted into the subarachnoid space through the intervertebral foramen between L5 and L6, according to the method described by Hylden and Wilcox (1980). For i.c.v. injection, the drugs were also administered in a volume of 5 μl via a disposable 27-gauge needle, which was inserted into the lateral ventricle (Haley and McCormick, 1957). The 5-HT receptor antagonists were administered 20 min before fluvoxamine injection.[2]

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Doses of 10 and 30 mg/kg of Fluvoxamine dissolved in saline were intraperitoneally administered in the single-injection group. In the repeated-treatment group, fluvoxamine (30 mg/kg), which was dissolved in deionized water in a volume of 5 ml/kg when used, was given orally once a day for 21 days. All administrations were performed between 09:00 and 11:00 h. On the 22nd day, repeated-treatment rats were systemically injected at a dose of 30 mg/kg of fluvoxamine dissolved in saline. [3]

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10 and 30 mg/kg, i.p.

Non-ligated mice

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]. Psychopharmacology (Berl). 2004 Nov;176(2):195-203.

[2]. Neuropharmacology. 2006 Sep;51(4):866-72.

[3]. Brain Res. 2002 Sep 13;949(1-2):131-8.

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

Fluvoxamine maleate is a member of (trifluoromethyl)benzenes.
Fluvoxamine Maleate is the maleate salt form of fluvoxamine, a 2-aminoethyl oxime ether of aralkylketones, with antidepressant, antiobsessive-compulsive, and antibulimic activities. Fluvoxamine blocks serotonin reuptake by inhibiting the serotonin reuptake pump of the presynaptic neuronal membrane leading to an increase of serotonin levels within the synaptic cleft. This results in facilitated serotonergic transmission and decreased serotonin turnover leading to antidepressant and antiobsessive-compulsive effects.
A selective serotonin reuptake inhibitor that is used in the treatment of DEPRESSION and a variety of ANXIETY DISORDERS.
See also: Fluvoxamine (has active moiety).

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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.

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Rationale: The combination of atypical antipsychotic drugs in addition to serotonin reuptake inhibitors has recently proven to be beneficial in a number of neuropsychiatric disorders, such as major depression, schizophrenia, and obsessive-compulsive disorder. Objectives: To investigate the effects of an atypical antipsychotic drug in combination with a serotonin reuptake inhibitor on extracellular serotonin [5-HT]ex, and dopamine levels [DA]ex in different brain areas. Methods: The effects of quetiapine (10 mg/kg) with fluvoxamine (10 mg/kg) on [5-HT]ex and [DA]ex were compared in the rat dorsal striatum, prefrontal cortex, nucleus accumbens (core and shell), and thalamus by means of microdialysis coupled to HPLC with electrochemical detection. Results: Quetiapine had no significant effect on [DA]ex and [5-HT]ex levels in the prefrontal cortex and thalamus, but increased [DA]ex and [5-HT]ex levels in the dorsal striatum. In the accumbens, quetiapine increased [DA]ex levels and decreased [5-HT]ex levels. Fluvoxamine increased [5-HT]ex levels in all brain areas, and also increased [DA]ex levels in the striatum. The combination of quetiapine with fluvoxamine increased [DA]ex and [5-HT]ex levels in all brain areas compared with baseline. Although neither quetiapine nor fluvoxamine in monotherapy affected [DA]ex levels in the prefrontal cortex and thalamus, the combination produced a significant increase of [DA]ex levels in these two brain areas. Conclusions: The combination of quetiapine with fluvoxamine causes a synergistic dopamine increase in the prefrontal cortex and the thalamus. [1]

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In summary, the combination of quetiapine and fluvoxamine causes a unique synergistic DA increase in the PFC and the THAL. It remains to be established whether such a synergistic increase of [DA]ex levels in the PFC and THAL can be related to the therapeutic efficacy of combination therapies of atypical APD with SSRIs.[1]

C19H25F3N2O6

434.41

434.166

C, 52.53; H, 5.80; F, 13.12; N, 6.45; O, 22.10

61718-82-9

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

9560989

White to off-white solid powder

370.6ºC at 760 mmHg

120-121.5ºC

177.9ºC

3.613

3

11

11

30

446

0

FC(C1C([H])=C([H])C(=C([H])C=1[H])/C(/C([H])([H])C([H])([H])C([H])([H])C([H])([H])OC([H])([H])[H])=N\OC([2H])([2H])C([2H])([2H])N([H])[H])(F)F.O([H])C(/C(/[H])=C(/[H])\C(=O)O[H])=O

LFMYNZPAVPMEGP-PIDGMYBPSA-N

InChI=1S/C15H21F3N2O2.C4H4O4/c1-21-10-3-2-4-14(20-22-11-9-19)12-5-7-13(8-6-12)15(16,17)18;5-3(6)1-2-4(7)8/h5-8H,2-4,9-11,19H2,1H3;1-2H,(H,5,6)(H,7,8)/b20-14+;2-1-

(Z)-but-2-enedioic acid;2-[(E)-[5-methoxy-1-[4-(trifluoromethyl)phenyl]pentylidene]amino]oxyethanamine

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Note: Please store this product in a sealed and protected environment, avoid exposure to moisture.

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

Solubility in Formulation 1: ≥ 2.5 mg/mL (5.75 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 25.0 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: ≥ 2.5 mg/mL (5.75 mM) (saturation unknown) 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.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 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: ≥ 2.5 mg/mL (5.75 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 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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Solubility in Formulation 4: 20 mg/mL (46.04 mM) in PBS (add these co-solvents sequentially from left to right, and one by one), clear solution; with ultrasonication.

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Solubility in Formulation 5: 20 mg/mL (46.04 mM) in phosphate buffer Saline (add these co-solvents sequentially from left to right, and one by one), clear solution; with ultrasonication.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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