sPLA2 ( Ki = 15 nM ); 5-HT_3A Receptor ( Ki = 3.7 nM ); Human 5-HT₇ Receptor ( Ki = 19 nM ); SERT ( Ki = 1.6 nM )
In vitro activity: Vortioxetine (Compound 5m) is a multimodal serotonergic agent that inhibits SERT with values of 1.6 nM, 33 nM, 3.7 nM, 19 nM, and 5-HT_1A, 5-HT_1B, and 5-HT₇ receptors, respectively. Vortioxetine exhibits strong suppression of SERT, partial agonist characteristics at 5-HT_1B and 5-HT_1A receptors, antagonistic properties at 5-HT_3A and 5-HT₇ receptors, and agonistic properties at 5-HT_1A receptors[1]. Using a whole-cell cAMP-based assay, vortioxetine is a partial h5-HT_1B receptor agonist with an EC50 of 460 nM and intrinsic activity of 22%. In vitro whole-cell cAMP assay, vortioxetine binds to the r5-HT₇ receptor with a K_i value of 200 nM and is a functional antagonist at the r5-HT₇ receptor with an IC50 of 2 μM[5].

In vitro activity: Vortioxetine (Compound 5m) is a multimodal serotonergic agent that inhibits SERT with values of 1.6 nM, 33 nM, 3.7 nM, 19 nM, and 5-HT_1A, 5-HT_1B, and 5-HT₇ receptors, respectively. Vortioxetine exhibits strong suppression of SERT, partial agonist characteristics at 5-HT_1B and 5-HT_1A receptors, antagonistic properties at 5-HT_3A and 5-HT₇ receptors, and agonistic properties at 5-HT_1A receptors[1]. Using a whole-cell cAMP-based assay, vortioxetine is a partial h5-HT_1B receptor agonist with an EC50 of 460 nM and intrinsic activity of 22%. In vitro whole-cell cAMP assay, vortioxetine binds to the r5-HT₇ receptor with a K_i value of 200 nM and is a functional antagonist at the r5-HT₇ receptor with an IC50 of 2 μM[5].

Vortioxetine (Lu AA21004) is a 5-HT₃ receptor antagonist that binds to the r5-HT_1B receptor and rSERT (ED50 = 3.2 and 0.4 mg/kg, respectively) when administered subcutaneously[6]. After 21 days of treatment, vortioxetine dramatically boosts immature granule cell maturation in the sub granular zone of the dentate gyrus of the hippocampus as well as cell survival and proliferation[3]. Cognitive or psychomotor impairment is not brought on by vortioxetine[4].

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Acute oral administration of Vortioxetine (5 mg/kg, 1h pre-test) to BALB/cJ mice produced anxiolytic-like effects in the open field test, increasing time spent in the center (p<0.05), number of center entries (p<0.05), and distance traveled in the center (p<0.05), comparable to diazepam (1.5 mg/kg). The 10 mg/kg dose was ineffective. [2]
Acute oral Vortioxetine (5 mg/kg, 1h pre-test) showed antidepressant-like activity in the forced swim test (FST) in BALB/cJ mice, increasing total mobility duration (p<0.01), swimming duration (p<0.01), and climbing duration (p<0.05). Fluoxetine (18 mg/kg) only increased swimming duration. [2]
Acute oral Vortioxetine (5 mg/kg, 1h pre-test) produced an anxiolytic-like effect in the novelty-suppressed feeding (NSF) test in 129S6/SvEvTac mice, significantly reducing the latency to feed (p<0.01), similar to diazepam. The 10 mg/kg dose was ineffective. Fluoxetine showed no significant effect. [2]
Chronic oral administration of Vortioxetine (5 mg/kg/day for 21 days, tested 24h after last dose) to BALB/cJ mice produced sustained anxiolytic-like effects in the open field test (increased time in center, p<0.01; increased center entries, p<0.05) and antidepressant-like effects in the FST (increased mobility, p<0.01; swimming, p<0.01; climbing, p<0.05). The 20 mg/kg/day dose was ineffective. Chronic fluoxetine (18 mg/kg/day) was inactive in these tests. [2]
Chronic oral Vortioxetine (5 mg/kg/day for 21 days, tested 24h after last dose) reduced latency to feed in the NSF test in 129S6/SvEvTac mice (p<0.05). When administered for 14 days, the 20 mg/kg/day dose was effective (p<0.01), but the 5 mg/kg/day dose was not. Chronic fluoxetine was ineffective at both time points. [2]
Chronic Vortioxetine (5 mg/kg/day p.o. for 21 days) in 129S6/SvEvTac mice significantly increased cell proliferation (BrdU+ cells, p<0.05) and cell survival (BrdU+ cells, p<0.05) in the hippocampal dentate gyrus. [2]
Chronic Vortioxetine (5 and 20 mg/kg/day p.o. for 21 days) increased the number of doublecortin-positive (DCX+) neurons with tertiary dendrites (p<0.05 for both doses) and the neuronal maturation index (ratio of DCX+ cells with tertiary dendrites to total DCX+ cells; p<0.05 for 5 mg/kg, p<0.0001 for 20 mg/kg) in the dentate gyrus. Fluoxetine also increased these parameters. [2]
Chronic Vortioxetine (20 mg/kg/day p.o. for 14 days) increased dendritic length (p<0.0001) and the number of dendritic intersections (p<0.0001) in DCX+ neurons with tertiary dendrites, as measured by Sholl analysis. [2]
Ex vivo autoradiography showed that acute Vortioxetine (5 and 10 mg/kg p.o., 1h) produced 60-70% SERT occupancy and >90% 5-HT3 receptor occupancy in mouse brain at the time of behavioral testing. [2]
After chronic dosing (5 or 20 mg/kg/day for 14 or 21 days) and testing 24h after the last dose, Vortioxetine showed minimal SERT occupancy (≈0-14%) and low 5-HT3 receptor occupancy (≈8-42%, significant only for 20 mg/kg in BALB/cJ at 21 days), in contrast to fluoxetine which maintained >90% SERT occupancy. [2]

Vortioxetine (Compound 5m) is a multimodal serotonergic agent that inhibits SERT with values of 1.6 nM, 33 nM, 3.7 nM, 19 nM, and 5-HT1A, 5-HT1B, and 5-HT7 receptors, respectively. Vortioxetine exhibits strong suppression of SERT as well as antagonistic effects at 5-HT3A and 5-HT7 receptors, partial agonist effects at 5-HT1B receptors, and agonistic effects at 5-HT1A receptors.

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Compound 5m (Lu AA21004) was the lead compound, displaying high affinity for recombinant human 5-HT(1A) (K(i) = 15 nM), 5-HT(1B) (K(i) = 33 nM), 5-HT(3A) (K(i) = 3.7 nM), 5-HT(7) (K(i) = 19 nM), and noradrenergic β(1) (K(i) = 46 nM) receptors, and SERT (K(i) = 1.6 nM). Compound 5m displayed antagonistic properties at 5-HT(3A) and 5-HT(7) receptors, partial agonist properties at 5-HT(1B) receptors, agonistic properties at 5-HT(1A) receptors, and potent inhibition of SERT.[1]

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Ex vivo SERT and 5-HT3 receptor occupancy assays[2]
Brains from mice treated with vehicle, fluoxetine, or vortioxetine (1 h after acute administration or 24 h after the 14th or 21st injection) were flash frozen, sectioned coronally using a cryostat, and then mounted on slides and frozen until use. Slices were 20 μm thick, and began at approximately +1.2 mm anterior from bregma for SERT receptor occupancy or −2.7 mm posterior from bregma for 5-HT3 receptor occupancy determination (Franklin and Paxinos, 2008). Slides were stored for at least 24 h at −20 °C before use in autoradiography experiments.

Vortioxetine is a partial h5-HT1B receptor agonist that, in a whole-cell cAMP-based assay, has an EC50 of 460 nM and an intrinsic activity of 22%. In vitro whole-cell cAMP assay, vortioxetine binds to the r5-HT7 receptor with a Kivalue of 200 nM and is a functional antagonist at the r5-HT7 receptor with an IC50 of 2 μM.

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Assessment of SERT occupancy[2]
Slides were incubated at room temperature for 60 min in buffer (50 mM Tris–HCl, 150 mM NaCl, 5 mM KCl, pH = 7.4) containing 4.5 nM [3H]-escitalopram. Nonspecific binding was determined using 1 μM escitalopram. Slides were washed briefly in cold buffer, dried, and exposed in a Beta imager for 16 h. The region of interest (ROI) for the SERT assay included the lateral and medial septum, the nucleus accumbens and the olfactory tubercle. An example image of the ROI for the SERT assay can be found in Supplementary Fig. 2A.

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Assessment of 5-HT3 receptor occupancy[2]
Slides were preincubated for 5 min in a buffer consisting of 50 mM Tris and 150 mM NaCl. Slides were dried under a stream of air for 30–45 min. Subsequently, slides were incubated at room temperature for 60 min in buffer (50 mM Tris–HCl, 150 mM NaCl, 5 mM KCl, pH = 7.4) containing 1 nM [3H]LY278584. Nonspecific binding was determined using 1 μM ondansetron. Slides were washed briefly in cold buffer, dried, and exposed in a Beta imager for 24 h. The ROI for the 5-HT3 receptor occupancy assay consisted of the hippocampus. An example image for the 5-HT3 receptor occupancy assay can be found in Supplementary Fig. 2B .

Dissolved in 10% hydroxypropyl-β-cyclodextrin; 10 mg/kg; s.c. administrationRats Acute studies[2]
Three doses of vortioxetine (2.5, 5 and 10 mg/kg, free base dissolved in 10% β-cyclodextrin, oral gavage, p.o.,) were used in the OF test, the NSF test and the FST. The effects of vortioxetine were compared to the vehicle control group (10% β-cyclodextrin) and also to a fluoxetine- (18 mg/kg p.o., (David et al., 2007)) and a diazepam-treated group (1.5 mg/kg, s.c. (David et al., 2007)). All doses were corrected for the weight of the salt. All treatments were administered 1 h before testing.

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Chronic studies[2]
Two doses of vortioxetine (5 and 20 mg/kg/day, free base dissolved in 10% β-cyclodextrin, oral gavage, p.o.) were tested in mice after 14 days of administration in the NSF and 21 days of administration in the OF test, the NSF test and the FST. The mice were tested 24 h after the last dose. The effects of vortioxetine were compared to a vehicle control group (10% β-cyclodextrin) and also to a fluoxetine-treated group (18 mg/kg/day p.o.).

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For acute behavioral studies, Vortioxetine (free base) was dissolved in 10% β-cyclodextrin and administered orally (p.o.) by gavage at doses of 2.5, 5, or 10 mg/kg. Behavioral tests (open field, forced swim test, novelty-suppressed feeding) were conducted 1 hour after administration. Control groups received vehicle (10% β-cyclodextrin), fluoxetine (18 mg/kg p.o.), or diazepam (1.5 mg/kg s.c.). [2]
For chronic behavioral and neurogenesis studies, Vortioxetine (5 or 20 mg/kg/day, free base in 10% β-cyclodextrin) was administered orally once daily for 14 or 21 days. Behavioral tests were conducted 24 hours after the last dose. The control group received vehicle or fluoxetine (18 mg/kg/day p.o.). [2]
For neurogenesis assessment, cell proliferation was studied by injecting BrdU (150 mg/kg, i.p.) 2 hours before sacrifice. Cell survival was studied by injecting BrdU (150 mg/kg, i.p., twice daily for 3 days) 4 weeks before sacrifice. Brains were collected, and immunohistochemistry was performed for BrdU and doublecortin (DCX) to label newborn neurons. DCX+ cells were categorized, and a maturation index (ratio of DCX+ cells with tertiary dendrites to total DCX+ cells) was calculated. Dendritic complexity of DCX+ neurons with tertiary dendrites was analyzed using Sholl analysis. [2]
For ex vivo receptor occupancy assays, brains from treated mice were flash-frozen, sectioned, and mounted. For SERT occupancy, slides were incubated with 4.5 nM [³H]-escitalopram. For 5-HT3 receptor occupancy, slides were incubated with 1 nM [³H]Y-278584. Non-specific binding was determined using escitalopram (1 µM) or ondansetron (1 µM), respectively. Slides were washed, dried, and exposed to a Beta imager. Radioactivity was quantified in predefined regions of interest. [2]

Absorption, Distribution and Excretion
Following administration, the maximum plasma concentration (Cmax) of vortioxetine was reached within 7 to 11 hours. The absolute bioavailability was 75%. No effect of food on pharmacokinetics was observed. Following a single oral administration of [14C]-labeled vortioxetine, approximately 59% and 26% of the administered radioactivity, respectively, were recovered as metabolites in urine and feces. The amount of unmetabolized vortioxetine excreted in urine within 48 hours was negligible. The apparent volume of distribution of vortioxetine is approximately 2600 liters, indicating its extensive extravascular distribution. /Breast Milk/ It is unclear whether vortioxetine is present in human breast milk. Vortioxetine is present in the breast milk of lactating rats. Vortioxetine is a novel multimodal drug for the treatment of major depressive disorder, exhibiting high affinity for multiple different serotonergic targets in the central nervous system. We report the (11)C labeling of vortioxetine with (11)C-MeI using the Suzuki conjugation protocol, which allows for the presence of unprotected amino groups. Preliminary evaluation of (11)C-vortioxetine in Danish Landrace pigs showed rapid uptake and distribution in the brain, consistent with its pharmacological profile, although unexpectedly high binding was also observed in the cerebellum. (11)C-vortioxetine exhibited slow tracer kinetics, reaching peak uptake after 60 minutes, with limited clearance from the brain. Further research is needed, but this radioligand could be a valuable tool for elucidating the clinical efficacy of vortioxetine. Vortioxetine and its related substances are primarily excreted via feces in mice (84%), rats (69%), and dogs (59% and 65% in two independent studies, respectively), while in humans, it is primarily excreted via urine (59%), with less fecal excretion (26%). In excretion studies, the recovery rates of vortioxetine and its related compounds in rodents were close to 100%. Excretion in dogs and humans was slower, with recoveries of approximately 90% and 85% after 168 hours and 360 hours, respectively. This study aimed to characterize the pharmacokinetics of vortioxetine and assess the effects of intrinsic and extrinsic factors on healthy individuals. Data from 26 clinical pharmacology studies were compiled. A total of 21,758 measurable plasma concentrations of vortioxetine were collected from 887 subjects with corresponding demographic characteristics. Dosage ranges were 2.5 to 75 mg (single dose) and 2.5 to 60 mg (once daily, multiple doses). The pharmacokinetic profile of vortioxetine best fit a two-compartment model, which includes first-order absorption, lag time, and linear elimination, and accounts for inter-individual error terms for the absorption rate constant, oral clearance, and central volume of distribution. The population mean oral clearance was 32.7 L/hr, and the population mean central volume of distribution was 1.97 × 10³ L. The mean elimination half-life was 65.8 hours. Statistically significant covariate-parameter relationships were found between CYP2D6-inferred metabolic status (ultra-rapid metabolizer, rapid metabolizer, intermediate metabolizer, or slow metabolizer) and age with oral clearance, and between height and central volume of distribution. For individuals with lower CYP2D6 metabolic capacity, the CL/F value was approximately 50% of that of individuals with higher CYP2D6 metabolic capacity. Height had a small effect on V2/F value, and age had a small effect on CL/F value, which was not clinically significant. The final model was proven to be reliable, stable, and predictive. We developed a reliable, stable, and predictive pharmacokinetic model to characterize the pharmacokinetic properties of vortioxetine in healthy individuals.
For more complete data on the absorption, distribution, and excretion of vortioxetine (10 parameters), please visit the HSDB record page.
Metabolism/Metabolites
Vortioxetine is extensively metabolized primarily through oxidation by cytochrome P450 isoenzymes CYP2D6, CYP3A4/5, CYP2C19, CYP2C9, CYP2A6, CYP2C8, and CYP2B6, followed by glucuronide conjugation. CYP2D6 is the major enzyme catalyzing the metabolism of vortioxetine into a pharmacologically inactive carboxylic acid metabolite. The plasma concentration of vortioxetine is approximately twice that of individuals with low CYP2D6 metabolic capacity compared to those with high metabolic capacity.
Vortioxetine is extensively metabolized primarily through oxidation by cytochrome P450 isoenzymes CYP2D6, CYP3A4/5, CYP2C19, CYP2C9, CYP2A6, CYP2C8, and CYP2B6, followed by glucuronide conjugation. CYP2D6 is the major enzyme catalyzing the metabolism of vortioxetine into a pharmacologically inactive carboxylic acid metabolite. The plasma concentration of vortioxetine is approximately twice that of individuals with low CYP2D6 metabolic capacity compared to those with high metabolic capacity. All metabolites detected in human hepatocytes, except for the monohydroxyvortioxetine glucuronide conjugate, were found in dogs, mice, and rats (plasma and/or urine), while the monohydroxyvortioxetine glucuronide conjugate was not found in mice and rats. Among all tested species, the metabolite profile of rabbit hepatocytes appears to be the closest to that of human hepatocytes. The mean terminal half-life is approximately 66 hours. The absolute oral bioavailability in rats, dogs, and patients is approximately 10%, 48%, and 75%, respectively, with corresponding terminal elimination half-lives of 3.0 hours, 7.9 hours, and 66 hours. …Data from 26 clinical pharmacology studies are summarized. A total of 21,758 quantifiable plasma concentrations of vortioxetine were collected from 887 subjects with corresponding demographic characteristics. The dosage range was 2.5 to 75 mg (single dose) and 2.5 to 60 mg (once daily multiple doses). …The mean elimination half-life was 65.8 hours. The mean elimination half-life and oral clearance were 66 hours and 33 L/hour, respectively. The half-life of vortioxetine in rats was approximately 3.2 hours, and there were no active metabolites at its target site. [2]

Toxicity Summary
Identification and Uses: Vortioxetine is a white to micron-colored powder, formulated as film-coated tablets. It is used to treat major depressive disorder in adults. Human Exposure and Toxicity: Clinical experience with human overdose of vortioxetine is limited. In premarketing clinical studies, overdose cases were limited to patients who accidentally or intentionally ingested no more than 40 mg of vortioxetine. The maximum single test dose for male subjects was 75 mg. Administration of vortioxetine in the dose range of 40 to 75 mg was associated with an increased incidence of nausea, dizziness, diarrhea, abdominal discomfort, generalized itching, drowsiness, and flushing. Toxicity can also occur at therapeutic dose levels of vortioxetine. It has been reported that the use of serotonergic antidepressants alone (including vortioxetine) can cause life-threatening serotonin syndrome, especially when used concurrently with other serotonergic drugs (including serotonin (5-HT) type 1 receptor agonists (“triptans”), tricyclic antidepressants, buspirone, fentanyl, lithium, tramadol, tryptophan, and St. John's wort) and drugs that impair serotonin metabolism (particularly monoamine oxidase (MAO) inhibitors, including those used to treat mental illness and others such as linezolid and methylene blue). Clinical manifestations of serotonin syndrome may include altered mental status (e.g., agitation, hallucinations, delirium, and coma), autonomic dysfunction (e.g., tachycardia, blood pressure fluctuations, dizziness, excessive sweating, flushing, and high fever), neuromuscular symptoms (e.g., tremor, rigidity, myoclonus, hyperreflexia, and incoordination), seizures, and/or gastrointestinal symptoms (e.g., nausea, vomiting, and diarrhea). Concomitant or recent (i.e., within 2 weeks) use of monoamine oxidase inhibitors (MAO inhibitors) for the treatment of mental illness is contraindicated. Use of MAO inhibitors for the treatment of mental illness within 3 weeks of discontinuing vortioxetine is also contraindicated. Furthermore, patients receiving other MAO inhibitors (such as linezolid or intravenous methylene blue) should not begin taking vortioxetine. If concomitant use of vortioxetine and other serotonergic drugs is clinically necessary, patients should be informed of the potential increased risk of serotonin syndrome, especially at the beginning of treatment or when increasing the dose. Short-term studies have shown that antidepressants increase the risk of suicidal ideation and behavior in children, adolescents, and young adults. These studies did not show an increased risk of suicidal ideation and behavior in patients over 24 years of age; there was a trend towards a reduced risk in patients 65 years of age and older. Vortioxetine did not show genotoxicity in in vitro human lymphocyte chromosome aberration assays. Animal studies: The acute single-dose toxicity of vortioxetine is relatively low, with maximum tolerated doses (MTDs) of 300 mg/kg in mice and 500 mg/kg in rats. Rats administered 500 mg/kg showed clinical symptoms including marked sensitivity to touch and disturbances, rapid breathing, and brown staining around the nose. Mice administered 200 and 300 mg/kg showed tremors, tactile sensitivity, half-closed eyes, and decreased activity; those administered 400 and 500 mg/kg showed rapid breathing, coarse breath sounds and/or dyspnea, incoordination, unsteady gait, tilting, salivation, and hyperactivity. Administering vortioxetine (200 mg/kg) twice at one-hour intervals resulted in clinical symptoms, including seizures, ultimately leading to death. In carcinogenicity studies, mice and rats were orally administered vortioxetine at doses up to 50 and 100 mg/kg/day in males and females, respectively, and up to 40 and 80 mg/kg/day in males and females, respectively, for two years. The incidence of benign rectal polypoid adenomas was significantly higher in female rats than in male rats. These polypoid adenomas are thought to be associated with inflammation and hyperplasia and may be caused by interactions of excipient components in the formulation used in the study. This phenomenon was not observed in male rats. In mice, vortioxetine was not carcinogenic in either male or female mice. Administration of vortioxetine during pregnancy in rats and rabbits resulted in developmental delay. Rats given vortioxetine during pregnancy and lactation also showed developmental delay after birth. No teratogenic effects were observed in rats or rabbits given vortioxetine during organogenesis. Administration of vortioxetine to rats at doses up to 120 mg/kg/day had no effect on the fertility of either male or female rats. Vortioxetine did not show genotoxicity in the in vitro bacterial reverse mutation assay (Ames test) and the in vivo rat bone marrow micronucleus assay.

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Hepatotoxicity
A small number of patients may experience abnormal liver function (
Probability score: E (unproven but suspected rare cause of clinically significant liver injury)).

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Use during pregnancy and lactation
◉ Overview of use during lactation
The amount of vortioxetine in breast milk appears to be very low. If a mother needs to take vortioxetine, there is no need to stop breastfeeding. However, the infant should be closely monitored while breastfeeding and taking vortioxetine until more data are available.
◉ Effects on breastfed infants
Three breastfeeding mothers are taking vortioxetine to treat depression; two are taking 10 mg daily, one is taking…20 mg once daily. All mothers exclusively breastfed their infants at 1, 2, and 6 months of age. No mothers reported any abnormal behavior in their infants.
One woman taking vortioxetine at a daily dose of 76.1 μg/kg partially breastfed her infant. She did not observe any adverse reactions in her infant.
A Japanese postpartum woman with depression took 20 mg of vortioxetine, 10 mg of zolpidem, 20 mg of duloxetine, 100 mg of rebamipide, and 2.5 g of the Asian herbal medicine Shinki-yu daily. She breastfed her infant partially (over 50%) for 3 months. No drug-related adverse reactions were detected in the infant during routine follow-ups at 1, 3, 5, 7, and 9 months postpartum.
◉ Effects on Lactation and Breast Milk
Vortioxetine has caused hyperprolactinemia and galactorrhea in some patients.
An observational study investigated the outcomes of 2,859 women who took antidepressants for 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. Mothers who took antidepressants only in the first and second trimesters were not less likely to breastfeed at discharge. This 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 who took antidepressants in late pregnancy (n = 575) with women with mental illness who did not take antidepressants (n = 1552) and mothers who were not diagnosed with mental illness (n = 30,535). Women taking antidepressants 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. None of the mothers were taking vortioxetine. In a study of 80,882 Norwegian mother-infant pairs from 1999 to 2008, 392 women reported starting antidepressants postpartum, and 201 women reported starting antidepressants during pregnancy. Compared to the control group unexposed 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 exclusive breastfeeding. Compared to the control group unexposed to antidepressants, starting or restarting antidepressant use was associated with a 63% lower likelihood of initiating breastfeeding. Major adverse events included a 51% lower likelihood of breastfeeding at 6 months and a 2.6-fold increased risk of abrupt cessation of breastfeeding. No specific antidepressant was mentioned.

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Protein Binding
Vortioxetine has a plasma protein binding rate of 98% in humans, independent of plasma concentration. There was no significant difference in plasma protein binding rate between healthy subjects and subjects with impaired liver function (mild, moderate) or kidney function (mild, moderate, severe, end-stage renal disease).

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Interactions
Patients currently receiving or recently receiving monoamine oxidase (MAO) inhibitors may experience potentially serious, sometimes fatal, adverse reactions if they subsequently start serotonergic antidepressants, or if they received SSRIs or SNRIs shortly before starting an MAO inhibitor. Caution should be exercised when using vortioxetine in combination with MAO inhibitors used to treat mental illness. Contraindicated. Furthermore, at least a 2-week interval should be observed between discontinuing a MAOI for mental illness and starting vortioxetine, and at least a 3-week interval should be observed between discontinuing vortioxetine and starting another MAOI for mental illness.
Concomitant use of vortioxetine with selective serotonin reuptake inhibitors (SSRIs) or selective serotonin and norepinephrine reuptake inhibitors (SNRIs) increases the risk of serious and potentially fatal serotonin syndrome. If concomitant use of vortioxetine with an SSRI or SNRI is clinically necessary, patients should be informed of the increased risk of serotonin syndrome, especially at the beginning of treatment and during dose escalation. If symptoms of serotonin syndrome occur, vortioxetine and the concurrently administered SSRI or SNRI should be discontinued immediately. Supportive and symptomatic treatment should be initiated immediately. Concomitant use of vortioxetine and diuretics may increase the risk of hyponatremia. When vortioxetine is taken concomitantly with carbamazepine (a potent CYP inducer) for more than 14 days, an increase in the vortioxetine dose should be considered. The manufacturer recommends that the maximum dose of vortioxetine should not exceed three times the original dose. After discontinuing carbamazepine, the original dose of vortioxetine should be resumed within 14 days. For more complete data on vortioxetine interactions (26 items in total), please visit the HSDB record page.

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Compared to excipients, long-term administration of vortioxetine (5 or 20 mg/kg/day, orally, for 14 or 21 days) did not result in a significant decrease in body weight in mice. Control. [2]

[1]. Discovery of 1-[2-(2,4-dimethylphenylsulfanyl)phenyl]piperazine (Lu AA21004): a novel multimodal compound for the treatment of major depressive disorder. J Med Chem. 2011 May 12;54(9):3206-21.

[2]. Antidepressant and anxiolytic potential of the multimodal antidepressant vortioxetine (Lu AA21004) assessed by behavioural and neurogenesis outcomes in mice. Neuropharmacology. 2013 May 28;73C:147-159.

[3]. A randomized trial on the acute and steady-state effects of a new antidepressant, vortioxetine (Lu AA21004), on actual driving and cognition. Clin Pharmacol Ther. 2013 Jun;93(6):493-501.

[4]. Vortioxetine (Lu AA21004) 5mg in generalized anxiety disorder: results of an 8-week randomized, double-blind, placebo-controlled clinical trial in the United States. Eur Neuropsychopharmacol. 2012 Dec;22(12):858-66.

[5]. Pharmacological effects of Lu AA21004: a novel multimodal compound for the treatment of major depressive disorder. J Pharmacol Exp Ther. 2012 Mar;340(3):666-75.

Therapeutic Uses
Anti-anxiety medication; 5-HT1 receptor agonist; 5-HT1 receptor antagonist; 5-HT3 receptor antagonist; serotonin reuptake inhibitor.
/Clinical Trials/ ClinicalTrials.gov is a registry and results database that indexes human clinical studies funded by public and private institutions worldwide. The website is maintained by the National Library of Medicine (NLM) and the National Institutes of Health (NIH). Each record on ClinicalTrials.gov includes a summary of the study protocol, including: the disease or condition; the intervention (e.g., the medical product, behavior, or procedure under investigation); the study title, description, and design; participation requirements (eligibility criteria); the location of the study; contact information for the study location; and links to relevant information from other health websites, such as the NLM's MedlinePlus (which provides patient health information) and PubMed (which provides citations and abstracts of academic articles in the medical field). Vortioxetine is indexed in the database.
Brintellix is indicated for the treatment of major depressive disorder (MDD). The efficacy of Brintellix has been demonstrated in six studies lasting 6 to 8 weeks (including one study in older adults) and one maintenance treatment study in adults. /Included on US product label/

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Drug Warnings
/Black Box Warning/ Warning: Suicidal thoughts and behaviors. Short-term studies have shown that antidepressants increase the risk of suicidal thoughts and behaviors in children, adolescents, and young adults. These studies did not show an increased risk of suicidal thoughts and behaviors in patients 24 years of age and older; the risk trended downward after starting antidepressant treatment in patients 65 years of age and older. Patients of all ages should be closely monitored for worsening of their condition and for the occurrence of suicidal thoughts and behaviors once they begin antidepressant treatment. Family members and caregivers should be informed of the importance of closely monitoring the patient's condition and communicating with the prescribing physician. Brintellix has not been evaluated for use in pediatric patients.
Life-threatening serotonin syndrome has been reported when serotonergic antidepressants (including vortioxetine) are used alone, especially when used concurrently with other serotonergic drugs (including serotonin (5-HT) type 1 receptor agonists (“triptans”), tricyclic antidepressants, buspirone, fentanyl, lithium, tramadol, tryptophan, and St. John's wort) and drugs that impair serotonin metabolism (particularly monoamine oxidase (MAO) inhibitors, including those used to treat mental illness and others such as linezolid and methylene blue). Clinical manifestations of serotonin syndrome may include altered mental status (e.g., agitation, hallucinations, delirium, coma), autonomic dysfunction (e.g., tachycardia, blood pressure fluctuations, dizziness, excessive sweating, flushing, high fever), neuromuscular symptoms (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination), seizures, and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). Patients taking vortioxetine should be monitored for serotonin syndrome. Concomitant or recent (within 2 weeks) use of monoamine oxidase inhibitors (MAO inhibitors) for the treatment of mental illness is prohibited. MAO inhibitors for the treatment of mental illness should also be prohibited for 3 weeks after discontinuation of vortioxetine. Vortioxetine should not be started in patients receiving other MAO inhibitors, such as linezolid or intravenous methylene blue. If concomitant use of vortioxetine and other serotonergic drugs is clinically necessary, patients should be informed of the increased risk of serotonin syndrome, especially at the beginning of treatment or with dose increases. If symptoms of serotonin syndrome occur, vortioxetine and any concomitant serotonergic drugs should be discontinued immediately, and supportive and symptomatic treatment should be initiated. Serotonergic antidepressants, including vortioxetine, may increase the risk of bleeding events. Concomitant use of aspirin, nonsteroidal anti-inflammatory drugs (NSAIDs), warfarin, and other anticoagulants may increase this risk. Case reports and epidemiological studies have shown an association between the use of drugs that interfere with serotonin reuptake and the occurrence of gastrointestinal bleeding. Bleeding events associated with medications that inhibit serotonin reuptake include ecchymosis, hematoma, epistaxis, and petechiae, and even life-threatening bleeding. Manufacturers advise informing patients that concurrent use of vortioxetine with aspirin or other nonsteroidal anti-inflammatory drugs (NSAIDs), warfarin, or other medications that affect clotting or bleeding increases the risk of bleeding. Treatment with serotonergic drugs, including vortioxetine, can lead to hyponatremia. In many cases, hyponatremia appears to be caused by syndrome of dysregulation of antidiuretic hormone secretion (SIADH). A premarketing study reported a case of hyponatremia with serum sodium concentrations below 110 mmol/L after taking vortioxetine. The risk of hyponatremia may be higher in older adults and patients taking diuretics or with other hypovolemia when taking serotonergic antidepressants. Signs and symptoms of hyponatremia include headache, poor concentration, memory loss, confusion, weakness, and unsteady gait, which may lead to falls; more severe and/or acute cases may even result in hallucinations, syncope, seizures, coma, respiratory arrest, and death. For patients with symptomatic hyponatremia, vortioxetine should be discontinued and appropriate medical intervention should be initiated.
For more complete data on vortioxetine (18 of these), please visit the HSDB record page.

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Pharmacodynamics
Vortioxetine has a high affinity for the human serotonin transporter (Ki = 1.6 nM), but no affinity for norepinephrine (Ki = 113 nM) or dopamine (Ki > 1000 nM) transporters. Vortioxetine potently and selectively inhibits serotonin reuptake by inhibiting the serotonin transporter (IC50 = 5.4 nM). Specifically, vortioxetine binds to 5HT3 (Ki=3.7 nM), 5HT1A (Ki=15 nM), 5HT7 (Ki=19 nM), 5HT1D (Ki=54 nM), and 5HT1B (Ki=33 nM) receptors, and is a 5HT3, 5HT1D, and 5HT7 receptor antagonist, a 5HT1B receptor partial agonist, and a 5HT1A receptor agonist.

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Vortioxetine (Lu AA21004) is a novel investigational multimodal antidepressant. [2]
Its mechanism of action involves the binding of SERT inhibition and receptor activity (5-HT3, 5-HT7, 5-HT1D antagonism; 5-HT1B partial agonism; 5-HT1A agonism), resulting in increased extracellular levels of serotonin, norepinephrine, and dopamine in the prefrontal cortex and hippocampus of rats. [2]
In mice, the antidepressant and anxiolytic effects of vortioxetine were observed at doses with relatively low SERT occupancy (60-70% with acute administration and very low with chronic administration), suggesting that its efficacy may involve mechanisms other than SERT inhibition. [2]
Behavioral effects were associated with enhanced hippocampal neurogenesis, including increased proliferation, survival, and maturation of newborn neurons. [2]

C18H22N2S

298.45

298.15

C, 72.44; H, 7.43; N, 9.39; S, 10.74

508233-74-7

Vortioxetine hydrobromide; 960203-27-4; Vortioxetine-d8; 2140316-62-5; 1253056-29-9 (lactate)

9966051

Light yellow to yellow solid powder

1.2±0.1 g/cm3

424.8±45.0 °C at 760 mmHg

210.7±28.7 °C

0.0±1.0 mmHg at 25°C

1.643

4.26

1

3

3

21

316

0

S(C1C([H])=C([H])C(C([H])([H])[H])=C([H])C=1C([H])([H])[H])C1=C([H])C([H])=C([H])C([H])=C1N1C([H])([H])C([H])([H])N([H])C([H])([H])C1([H])[H]

YQNWZWMKLDQSAC-UHFFFAOYSA-N

InChI=1S/C18H22N2S/c1-14-7-8-17(15(2)13-14)21-18-6-4-3-5-16(18)20-11-9-19-10-12-20/h3-8,13,19H,9-12H2,1-2H3

1-[2-(2,4-dimethylphenyl)sulfanylphenyl]piperazine

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)

Solubility in Formulation 1: ≥ 2.5 mg/mL (8.38 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 (8.38 mM) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), suspension solution; with ultrasonication.
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 (8.38 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: 15% Captisol, pH 9: 10 mg/mL

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