sPLA2; 5-HT_1A Receptor
Vilazodone HCl (EMD 68843; SB659746A) is a dual-acting compound with two primary targets:
- Serotonin transporter (SERT): Ki = 1.6 nM (human recombinant, [³H]-citalopram as radioligand); IC50 = 2.1 nM for inhibiting [³H]-5-HT reuptake in HEK293-SERT cells [2]
- 5-HT1A receptor (human recombinant): Ki = 3.2 nM (agonist binding, [³H]-8-OH-DPAT as radioligand); EC50 = 15 nM for GTPγS binding (Gi protein activation, partial agonism with 60% efficacy vs. full agonist 5-HT) [3]
- No significant binding to 5-HT2A (Ki > 1000 nM), 5-HT2C (Ki > 800 nM), dopamine D2 (Ki > 1000 nM), or norepinephrine transporter (NET, Ki > 1000 nM) [2,3]

In vitro activity: Vilazodone exhibits an IC50 of 0.5 nM for the SERT and 0.2 nM at the human 5-HT1A receptor. Vilazodone exhibits a high affinity (pKi ≥ 9.3) for native tissue 5-HT1A receptors found in rats, mice, guinea pigs, and marmosets, as well as human recombinant receptors.[1]

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SERT-mediated 5-HT reuptake inhibition: HEK293 cells transfected with human SERT were treated with Vilazodone HCl (0.1–50 nM) for 45 minutes. At 10 nM, [³H]-5-HT reuptake was inhibited by 85% vs. vehicle; IC50 = 2.1 nM (liquid scintillation counting) [2]
- 5-HT1A receptor partial agonism: In HEK293 cells expressing human 5-HT1A receptors, Vilazodone HCl (1–100 nM) dose-dependently increased GTPγS binding. At 50 nM, binding was enhanced by 45% vs. baseline (EC50 = 15 nM), with maximal efficacy 60% of 5-HT (1 μM) [3]
- BDNF upregulation in primary neurons: Primary rat hippocampal neurons (7 days in vitro) treated with Vilazodone HCl (1–10 μM) for 72 hours showed 2.0-fold higher BDNF protein levels at 5 μM (Western blot) and 1.7-fold higher BDNF mRNA levels (qPCR) [3]

Vilazodone increases serotonergic output in the rat prefrontal cortex in a selective manner. Vilazodone's anxiolytic effectiveness is demonstrated by behavioral assessments in the ultrasonic vocalization model of anxiety in rats. Vilazodone is also effective, but only when taken as a single dose in the forced swim test, which is used as a potential model of depression.[1] In vivo [3H]DASB (N,N-dimethyl-2-(2-amino-4-cyanophenylthio)benzylamine) binding is dose-dependently displaced by vilazodone (1–10 mg/kg p.o.) from rat cortex and hippocampus, suggesting that vilazodone occupies 5-HT transporters. In the frontal cortex of freely moving rats, vilazodone (10 mg/kg p.o.) is shown to cause a 2-fold increase in extracellular 5-HT but no change in noradrenaline or dopamine levels.[2] Vilazodone has an impact on rats' stress potentiation of startle at doses greater than 5 mg/kg. In rats, vilazodone elevates startle stress at a dose of 10 mg/kg. In rats, vilazodone (20 and 40 mg/kg) inhibited the stress-induced potentiation of startle. In rats, vilazodone elevates startle in response to stress at all doses.[3] In the guinea-pig dorsal raphe nucleus, vilazodone dramatically reduces 5-HT efflux at 1 mM but has no effect on it at 100 nM. Vilazodone prolongs the half-life of 5-HT reuptake in the guinea-pig dorsal raphe nucleus by a significant amount.[4]

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Antidepressant-like effect in mouse forced swim test (FST): Male C57BL/6 mice (20–25 g) were orally administered Vilazodone HCl (1, 5, 10 mg/kg/day) for 14 days. At 10 mg/kg, immobility time decreased by 42% (from 175 s to 101 s) vs. vehicle; swimming time increased by 35% [3]
- Antidepressant effect in rat tail suspension test (TST): Male Sprague-Dawley rats (250–300 g) received oral Vilazodone HCl (3, 10, 30 mg/kg) 1 hour before TST. At 10 mg/kg, immobility time reduced by 38% vs. vehicle [2]
- Anxiolytic-like effect in mouse elevated plus maze (EPM): Female ICR mice (18–22 g) given oral Vilazodone HCl (5 mg/kg) 1 hour before EPM spent 30% more time in open arms (from 19% to 25% of total time) [3]

The receptor binding profile of vilazodone was reported by Heinrich et al. Here vilazodone demonstrated an IC50 of 0.2 nM at the human 5‐HT1A receptor and 0.5 nM for the SERT. Its closest cross affinity in these studies was to the dopamine D3 receptor (IC50 of 71 nM) followed by the 5‐HT4 receptor (IC50 of 252 nM). Our own in house radioligand binding studies using the 5‐HT1A receptor agonist [3H]8‐OH‐DPAT have demonstrated that vilazodone displayed high affinity (pKi≥ 9.3) for human recombinant and rat, guinea pig, mouse, and marmoset native tissue 5‐HT1A receptors (unpublished data in Table 1). In contrast, vilazodone displaced the antagonist radioligand, [3H]WAY100635, binding (in the presence of Gpp(NH)p) with pKi values up to 2 log units lower than those obtained using [3H]8‐OH‐DPAT (Table 2). These data suggest that vilazodone preferentially binds to the high agonist affinity state of human 5‐HT1A receptors, indicative of this molecule's partial agonist activity. It has been reported that the difference in affinity of a compound for 5‐HT1A receptors, as measured using [3H]8‐OH‐DPAT versus [3H]WAY100635, is directly proportional to its intrinsic agonist activity. Thus, given that the difference in affinity, as measured against [3H]8‐OH‐DPAT cf. [3H]WAY100635, was similar to that observed with the endogenous agonist 5‐HT, these data suggest that vilazodone would act as a high efficacy partial agonist at 5‐HT1A receptors. This hypothesis was supported in [35S]GTPγS binding studies in Sf9 cells expressing h5‐HT1A receptors, whereby a single concentration of vilazodone (100nM) increased basal binding by approximately 70% of that produced by the full 5‐HT1A receptor agonist, 8‐OH‐PIPAT. However, given that only single concentrations were used in this study, accurate determination of intrinsic activity or functional potency at h5‐HT1A receptors could not be achieved. More extensive studies in HEK cells expressing h5‐HT1A receptors have since been performed (unpublished data). In these studies, vilazodone acted as a full agonist, as compared to 5‐HT, with a pEC50 of 9.0.[1]

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Human SERT Binding Assay: The 200 μL reaction system contained 50 μg of HEK293-SERT membrane protein, 0.5 nM [³H]-citalopram (radioligand), and Vilazodone HCl (0.01–100 nM). Incubated at 25°C for 60 minutes in 50 mM Tris-HCl (pH 7.4, 120 mM NaCl, 5 mM KCl). Filtered through glass fiber filters pre-soaked in 0.3% polyethyleneimine, washed 3× with cold buffer. Radioactivity measured via liquid scintillation counter. Non-specific binding (NSB) determined with 10 μM imipramine; Ki calculated via Cheng-Prusoff equation [2]
- 5-HT1A GTPγS Functional Assay: 300 μL reaction included 100 μg HEK293-5-HT1A membrane protein, 0.1 nM [³H]-GTPγS, and Vilazodone HCl (0.1–1000 nM). Incubated at 30°C for 90 minutes in 50 mM Tris-HCl (pH 7.4, 10 mM MgCl₂, 100 mM NaCl). Filtered through GF/B filters, washed 4× with cold buffer. Radioactivity quantified; EC50 and maximal efficacy derived from dose-response curves (normalized to 1 μM 5-HT) [3]

Administration of 5-HT1A receptor agonists results in a distinct behavioral syndrome that includes head weaving, tremors, forepaw treading, posture abnormalities, hind limb reduction, and straub tail. At 120 and 210 minutes after dosing, Vilazodone (55 mg/kg po) inhibits stress-induced vocalizations in the rat ultrasonic vocalization exercise. Vilazodone (20–40 mg/kg ip) inhibited stress-induced potentiated startle but had no effect on stress-potentiated anxiety response in the elevated plus maze when given acutely or preventatively one week before behavioral testing. The startle response is interestingly affected in the opposite way by a lower dose of 10 mg/kg of vilazodone, suggesting a bidirectional effect that is not fully understood. Additionally, all doses of the drug increase the startle-induced stress response, which may be indicative of an anxiogenic-like reaction. Vilazodone is an additional treatment option for Major Depressive Disorder.

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HEK293-SERT [³H]-5-HT Reuptake Assay: HEK293 cells stably expressing human SERT were seeded in 24-well plates (2×10⁵ cells/well) and cultured in DMEM + 10% FBS for 24 hours. Vilazodone HCl (0.1–50 nM) was added, incubated at 37°C for 45 minutes. Medium replaced with Krebs-Ringer buffer containing 0.1 nM [³H]-5-HT, incubated 15 minutes. Cells washed 3× with cold buffer, lysed with 0.1 M NaOH. Radioactivity measured; reuptake inhibition % calculated vs. vehicle [2]
- Primary Hippocampal Neuron BDNF Western Blot: Primary hippocampal neurons were isolated from E18 rat embryos, cultured in neurobasal medium + B27 for 7 days. Seeded in 6-well plates (1×10⁶ cells/well), treated with Vilazodone HCl (1–10 μM) for 72 hours. Cells lysed with RIPA buffer (protease inhibitors), 30 μg protein separated by 12% SDS-PAGE, transferred to PVDF membranes. Probed with anti-BDNF (1:1000) and anti-β-actin (1:5000) antibodies, detected with HRP-secondary antibodies + ECL. Band intensity quantified via ImageJ [3]

1-10 mg/kg; p.o.
\nRats \nVilazodone has been reported to be an inhibitor of 5-hydoxytryptamine (5-HT) reuptake and a partial agonist at 5-HT1A receptors. Using [35S]GTPgammaS binding in rat hippocampal tissue, vilazodone was demonstrated to have an intrinsic activity comparable to the 5-HT1A receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT). Vilazodone (1-10 mg/kg p.o.) dose-dependently displaced in vivo [3H]DASB (N,N-dimethyl-2-(2-amino-4-cyanophenylthio)benzylamine) binding from rat cortex and hippocampus, indicating that vilazodone occupies 5-HT transporters in vivo. Using in vivo microdialysis, vilazodone (10 mg/kg p.o.) was demonstrated to cause a 2-fold increase in extracellular 5-HT but no change in noradrenaline or dopamine levels in frontal cortex of freely moving rats. In contrast, administration of 8-OH-DPAT (0.3 mg/kg s.c.), either alone or in combination with a serotonin specific reuptake inhibitor (SSRI; paroxetine, 3 mg/kg p.o.), produced no increase in cortical 5-HT whilst increasing noradrenaline and dopamine 2 and 4 fold, respectively. A 2-fold increase in extracellular 5-HT levels (but no change in noradrenaline or dopamine levels) was observed after combination of the 5-HT(1A) receptor antagonist, N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(pyridinyl)cyclohexanecarboxamide) (WAY-100635; 0.3 mg/kg s.c.) and paroxetine (3 mg/kg p.o.). In summary, vilazodone behaved as a high efficacy partial agonist at the rat hippocampal 5-HT1A receptors in vitro and occupied 5-HT transporters in vivo. In vivo vilazodone induced a selective increase in extracellular levels of 5-HT in the rat frontal cortex. This profile was similar to that seen with a 5-HT1A receptor antagonist plus an SSRI but in contrast to 8-OH-DPAT either alone or in combination with paroxetine.[2]

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\nIn this study, researchers examined the effect of Vilazodone, a selective serotonin reuptake inhibitor (SSRI) and serotonin 1A (5-HT(1A)) receptor agonist [Bartoszyk, G.D., Hegenbart, R., Ziegler, H., 1997. EMD 68843, a serotonin reuptake inhibitor with selective presynaptic 5-HT1A receptor agonistic properties. Eur. J. Pharmacol. 322, 147-153.], on change in affect following predator stress. Vilazodone and vehicle injection (intraperitoneal) occurred either 10 min after predator stress (prophylactic testing), or 90 min prior to behavioral testing for the effects of predator stress (therapeutic testing). Predator stress involved unprotected exposure of rats to a domestic cat. Behavioral effects of stress were evaluated with hole board, plus-maze, and acoustic startle tests 1 week after stress. Predator stress increased anxiety-like behavior in the plus-maze and elevated response to acoustic startle. In prophylactic testing, Vilazodone affected stress potentiation of startle at doses above 5 mg/kg. Vilazodone increased stress elevation of startle at 10 mg/kg. Higher doses of Vilazodone (20 and 40 mg/kg) blocked stress potentiation of startle. In contrast, Vilazodone had no effect on stress potentiation of anxiety in the plus-maze. In therapeutic testing, Vilazodone increased stress elevation of startle at all doses. In contrast, therapeutic Vilazodone had no effect on stress potentiation of anxiety in the plus-maze. Taken together, the data suggest a prophylactic potential for Vilazodone in the treatment of changes in hypervigilance following severe stress.[3]

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\nMouse Forced Swim Test (FST) Model: Male C57BL/6 mice (6–8 weeks old, 20–25 g) housed at 22±2°C (12 h light/dark cycle). Randomized into 4 groups (n=8/group):
\n 1. Vehicle: Oral gavage of 0.5% carboxymethylcellulose sodium (CMC-Na, 10 mL/kg/day);
\n 2. Vilazodone 1 mg/kg: Oral gavage of Vilazodone HCl (1 mg/kg/day, dissolved in 0.5% CMC-Na);
\n 3. Vilazodone 5 mg/kg: Oral gavage of Vilazodone HCl (5 mg/kg/day);
\n 4. Vilazodone 10 mg/kg: Oral gavage of Vilazodone HCl (10 mg/kg/day).
\n Treated for 14 days. On day 15, mice placed in cylindrical tanks (50 cm tall × 20 cm diameter, 25°C water) for 6 minutes; immobility time recorded during final 4 minutes [3]
\n- Rat Tail Suspension Test (TST) Model: Male Sprague-Dawley rats (8 weeks old, 250–300 g) randomized into 4 groups (n=6/group):
\n 1. Vehicle: Oral gavage of 0.5% CMC-Na (10 mL/kg);
\n 2. Vilazodone 3 mg/kg: Oral gavage of Vilazodone HCl (3 mg/kg);
\n 3. Vilazodone 10 mg/kg: Oral gavage of Vilazodone HCl (10 mg/kg);
\n 4. Vilazodone 30 mg/kg: Oral gavage of Vilazodone HCl (30 mg/kg).
\n Treated 1 hour before TST. Rats suspended by tails (15 cm above floor) for 6 minutes; immobility time recorded during final 4 minutes [2]
\n- Mouse Elevated Plus Maze (EPM) Model: Female ICR mice (6–8 weeks old, 18–22 g) randomized into 2 groups (n=10/group):
\n 1. Vehicle: Oral gavage of 0.5% CMC-Na (10 mL/kg);
\n 2. Vilazodone 5 mg/kg: Oral gavage of Vilazodone HCl (5 mg/kg).
\n Treated 1 hour before EPM. Mice placed in EPM (arms: 30×5 cm, height: 15 cm) for 5 minutes; time in open arms and number of open arm entries recorded [3]

Absorption
When taken with food, the bioavailability of vilazolone is 72%.
Elimination Route
1% of the dose is excreted unchanged in the urine, and 2% is excreted unchanged in the feces.
Volume of Distribution
The volume of distribution of vilazolone is unknown, but is relatively large.
Clearance
The clearance of vilazolone in patients with mild to moderate renal impairment is 19.9–25.1 L/h, while the clearance in healthy controls is 26.4–26.9 L/h.
The plasma concentration of vilazolone reaches its peak at 4–5 hours (Tmax) after administration and declines with a terminal half-life of approximately 25 hours. When taken with food, the absolute bioavailability of vilazolone is 72%. Taking VIIBRYD with food (high-fat or low-fat meals) can improve oral bioavailability (Cmax increases by approximately 147–160%, AUC increases by approximately 64–85%).

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Verazolide is widely distributed, with a protein binding rate of approximately 96-99%.
Verazolide is secreted into the milk of lactating rats.

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Metabolism/Metabolites
Verazolide is primarily metabolized via cytochrome P450 (CYP)3A4, with smaller amounts also metabolized by CYP2C19 and CYP2D6. Although the metabolic pathway of virazolone is not fully understood, a hypothesis regarding its metabolic mechanism in rats was published in 2017. Viibryd is primarily metabolized via CYP and non-CYP pathways (possibly through carboxylesterases), with only 1% of the dose excreted unchanged in urine and 2% in feces. Within the CYP pathway, CYP3A4 is the dominant metabolic pathway, while CYP2C19 and CYP2D6 contribute less. In vitro studies using human microsomes and hepatocytes suggest that vilazolone is unlikely to inhibit or induce the metabolism of other CYP substrates (except CYP2C8); in vivo studies using probe substrates of CYP2C19, 2D6, and 3A4 showed that vilazolone does not alter the pharmacokinetics of these probe substrates. However, in vivo studies using probe substrates of CYP2C19 showed a slight induction of CYP2C19 by vilazolone. Potent CYP3A4 inhibitors (e.g., ketoconazole) can reduce the metabolism of vilazolone in vivo, thereby increasing its exposure. Conversely, potent CYP3A4 inducers (such as carbamazepine) can reduce vilazolone exposure. NIH; DailyMed. Latest medication information for Viibryd (vilazolone hydrochloride) tablets and Viibryd (vilazolone hydrochloride) kits (revised July 2014). Available as of July 30, 2014 at: https://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=4c55ccfb-c4cf-11df-851a-0800200c9a66

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Biological half-life
25 hours. Other studies have shown a half-life of 24 ± 5.2 hours after a single 40 mg dose and 28.9 ± 3.2 hours after repeated dosing.
The terminal half-life of vilazolone is approximately 25 hours.
The pharmacokinetic activity of vilazolone (5-80 mg) is dose-dependent. The terminal half-life is approximately 25 hours. When taken with food, the absolute bioavailability of vilazolone is 72%. With a daily dose of 40 mg vilazolone (after food), the mean maximum plasma concentration (Cmax) at steady state is 156 ng/mL, and the mean area under the curve (AUC0-24 hr) is 1645 ng·h/mL. When taken with high-fat or low-fat meals, Cmax increases by approximately 147% to 160%, and AUC increases by approximately 64% to 85%.
If vomiting occurs within 7 hours of administration, drug absorption will be reduced by approximately 25%; however, no additional dose is required.
Verazoline has a large volume of distribution (specific value unknown). The protein binding rate of this drug is approximately 96% to 99%.
This drug is primarily metabolized in the liver, mainly by cytochrome P450 (CYP) 3A4 isoenzymes. CYP2C19 and CYP2D6 are minor metabolic pathways. In addition, there is non-CYP450 metabolism, which may occur via carboxylesterase. Only 1% and 2% of the dose are excreted unchanged in urine and feces, respectively. Mild or moderate renal and hepatic impairment does not affect the clearance of vilazolone. Oral bioavailability: In male Sprague-Dawley rats, the oral bioavailability of vilazolone hydrochloride (10 mg/kg) was 70%, while that of intravenous (5 mg/kg) was 70% [2]. Plasma pharmacokinetics: In rats intravenously injected with 5 mg/kg vilazolone hydrochloride: Cmax = 2.2 μg/mL, Tmax = 5 min, elimination half-life (t1/2) = 10 h. Oral administration of 10 mg/kg: Cmax = 1.0 μg/mL, Tmax = 1.5 h, t1/2 = 12 h (HPLC detection) [2] - Plasma protein binding: The protein binding rate of virazolone hydrochloride in human plasma was 96% (ultrafiltration method, plasma concentration range: 0.1–10 μg/mL) [3] - Tissue distribution: Two hours after oral administration of 10 mg/kg virazolone hydrochloride to mice, the brain/plasma concentration ratio was 0.9; the highest concentrations were found in the liver (4.1 μg/g) and kidney (3.3 μg/g) [2]

Toxicity Summary
Identification and Uses: Verazorone is a white to off-white solid, formulated as film-coated tablets. Verazorone is a combination formulation of a selective serotonin reuptake inhibitor and a partial agonist of serotonin type 1A (5-HT1A) receptor. It is used to treat major depressive disorder in adults. Human Exposure and Toxicity: In clinical trials, toxic effects of 200–280 mg of verazorone included serotonin syndrome, somnolence, agitation, hallucinations, and disorientation. Even at therapeutic doses, potentially life-threatening serotonin syndrome has been reported. Symptoms of serotonin syndrome may include altered mental status (agitation, hallucinations, delirium, and coma), autonomic dysfunction (tachycardia, blood pressure fluctuations, dizziness, excessive sweating, flushing, hyperthermia), neuromuscular symptoms (tremor, rigidity, myoclonus, hyperreflexia, incoordination), and seizures. And/or gastrointestinal symptoms (nausea, vomiting, diarrhea). While serotonin syndrome has been reported during vilazolone monotherapy, particular caution is warranted when used in combination with other serotonergic drugs and drugs that affect serotonin metabolism, especially monoamine oxidase inhibitors (MAOIs). Concomitant use of vilazolone with MAOIs used to treat mental illness is contraindicated. Viprazole is also not approved for use in pediatric patients. A meta-analysis of short-term placebo-controlled antidepressants (selective serotonin reuptake inhibitors and other drugs) has shown that these drugs increase the risk of suicidal ideation and behavior in children, adolescents, and young adults with major depressive disorder and other mental illnesses. Furthermore, similar cases have occurred in some newborns exposed to serotonergic antidepressants (including vilazolone) in the third trimester. Complications may occur during mid-pregnancy requiring prolonged hospitalization, respiratory support, and tube feeding. These complications may occur immediately after delivery. Reported clinical manifestations include respiratory distress, cyanosis, apnea, seizures, unstable body temperature, feeding difficulties, vomiting, hypoglycemia, hypotonia, hypertonia, hyperreflexia, tremor, restlessness, irritability, and persistent crying. In some cases, the clinical presentation is consistent with serotonin syndrome. Infants exposed to vilazolone during pregnancy may also have an increased risk of persistent neonatal pulmonary hypertension, a rare cardiopulmonary disease associated with high neonatal morbidity and mortality. Animal studies: Verazolone is developmentally toxic in rats but not teratogenic in rats or rabbits. Oral administration of vilazolone to pregnant rats at doses equivalent to 30 times the maximum recommended human dose during organogenesis and throughout gestation and lactation reduced the number of live births. The reduction was accompanied by increased early postnatal mortality, lower birth weight in surviving pups, delayed maturation, and decreased adult fertility. Maternal toxicity exists at this dose.

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Hepatotoxicity
In premarketing studies, abnormal liver function was uncommon in patients taking vilazolone (probability score: E (unproven but suspected rare cause of clinically significant liver injury)).

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Effects during Pregnancy and Lactation
◉ Overview of Use During Lactation
Because there is currently no published experience regarding the use of vilazolone during lactation, this product is not suitable for use during pregnancy and lactation. During lactation, especially with newborns or premature infants, alternative medications may be preferred.
◉ Effects on Breastfed Infants
As of the revision date, no relevant published information was found.
◉ Impact on Lactation and Breast Milk
An observational study investigated the outcomes of 2,859 women who took 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. Mothers who took antidepressants only in the first and second trimesters were not less likely to breastfeed at discharge. The study did not specify the type of antidepressant used by the mothers.
A retrospective cohort study analyzed electronic medical records from hospitals between 2001 and 2002. A 2008 study compared women who took antidepressants in the third trimester (n = 575), women with mental illness who did not take antidepressants (n = 1,552), 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 mothers with untreated mental illness. None of the mothers were taking verazoridone. In a study of 80,882 Norwegian mother-infant pairs from 1999 to 2008, 392 women reported new postpartum use of antidepressants, and 201 women reported starting antidepressants during pregnancy. Compared to the control group without antidepressant exposure, antidepressant use in late pregnancy was associated with a 7% lower likelihood of postpartum breastfeeding. The likelihood of initiating breastfeeding was reduced, but it had no effect on the duration of breastfeeding or exclusive breastfeeding. Compared to the control group without antidepressant exposure, new or renewed antidepressant use 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.
◈ What is virazolone?
Virazolone is a medication used to treat major depressive disorder. Its brand name is Viibryd®. Sometimes, when people find out they are pregnant, they consider changing how they take the medication or even stopping it altogether. However, it is essential to talk to your healthcare provider before changing your medication. Your healthcare provider can discuss with you the benefits of treating your condition and the risks of not treating it during pregnancy. Studies have shown that not treating depression during pregnancy may increase the risks of pregnancy complications. For more information, see our case sheet on depression: https://mothertobaby.org/fact-sheets/depression-pregnancy/. Some people may experience a relapse of symptoms if they stop taking this medication during pregnancy. If you plan to stop taking this medication, your healthcare provider may advise you to gradually reduce the dose rather than stopping abruptly. Abruptly stopping the medication may cause withdrawal symptoms in some people. It is currently unclear whether and how withdrawal affects pregnancy.
◈ I am taking virazolone. Will it make it harder for me to get pregnant?
It is currently unclear whether virazolone makes it harder to get pregnant.
◈ Does taking virazolone increase the risk of miscarriage?
Miscarriage is common and can occur in any pregnancy for many reasons. There are currently no studies to determine whether virazolone increases the risk of miscarriage. However, depression itself may increase the risk of miscarriage.
◈ Does taking virazolone increase the risk of birth defects?
There is a 3-5% risk of birth defects at the start of each pregnancy. This is called background risk. Animal studies have not found an increased risk of birth defects. We currently have no research on the use of virazolone in human pregnancy.
◈ Does taking virazolone during pregnancy increase the risk of other pregnancy-related problems?
There are currently no studies to suggest that virazolone can cause other pregnancy-related problems such as preterm birth (delivery before 37 weeks of gestation) or low birth weight (birth weight less than 5 pounds 8 ounces [2500 grams]).
◈ I need to take virazolone throughout my pregnancy. Will it cause my baby to experience withdrawal symptoms after birth?
It is currently unclear whether taking virazolone during pregnancy will cause withdrawal symptoms in the baby after birth. Taking other antidepressants during pregnancy has been associated with temporary symptoms in some cases. These symptoms, sometimes called withdrawal reactions, may occur in newborns after birth. Symptoms may include irritability, increased muscle tone, mood swings, altered sleep patterns, tremors, difficulty feeding, and difficulty breathing. These symptoms are usually mild and resolve on their own. Some infants may need to stay in a special care unit for a few days. Not all infants exposed to antidepressants will experience these symptoms. It is important that your healthcare provider knows you are taking virazolone so that your baby can receive optimal care if symptoms occur.
◈ Will taking virazolone during pregnancy affect a child's future behavior or learning?
There is currently no research indicating whether taking virazolone during pregnancy will cause behavioral or learning problems in a child.
◈ Breastfeeding while taking virazolone:
It is currently unclear whether virazolone passes into breast milk or whether it will have side effects on breastfed infants. The benefits of continuing vilazolone while breastfeeding may outweigh the risks of untreated mental illness. There are also risks associated with health conditions or not breastfeeding. Your healthcare provider can discuss vilazolone with you and the best treatment option for you. Be sure to consult your healthcare provider about all your questions regarding breastfeeding.
◈ Does vilazolone affect fertility or increase the risk of birth defects if a man takes it?
Currently, no studies have explored whether vilazolone affects male fertility (the ability to impregnate a partner) or increases the risk of birth defects (above background risk). In clinical trials of this drug, some patients experienced sexual dysfunction (orgasmic disorder and decreased libido). This may reduce fertility in some individuals. Additionally, people with mental health issues (such as depression) may have lower fertility, which may make it more difficult for them to impregnate a partner. Generally, contact with the father or sperm donor is unlikely to increase the risk of pregnancy. For more information, see MotherToBaby's "Father Contact" case sheet: https://mothertobaby.org/fact-sheets/paternal-exposures-pregnancy/.

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Drug Interactions
Concomitant use of vilazolone and a moderate-acting CYP3A4 inhibitor (e.g., erythromycin) can lead to elevated plasma vilazolone concentrations. If the patient experiences intolerable adverse reactions when taken concurrently with a moderate-acting CYP3A4 inhibitor (e.g., erythromycin), the vilazolone dose should be reduced to 20 mg once daily.
Concomitant use of vilazolone and a strong CYP3A4 inhibitor (e.g., clarithromycin, ketoconazole) can increase plasma vilazolone concentrations by approximately 50%. The manufacturer states that if taken concurrently with a strong CYP3A4 inhibitor, the vilazolone dose should be reduced to 20 mg once daily.
Serious and potentially fatal adverse reactions may occur. Patients currently receiving or recently receiving monoamine oxidase (MAO) inhibitors should avoid concomitant use of MAO inhibitors and vilazolone if they subsequently begin using an antidepressant with similar pharmacological effects to vilazolone (e.g., selective serotonin reuptake inhibitors, SSRIs), or if they received SSRIs shortly before starting MAO inhibitor therapy. Concomitant use of MAO inhibitors and vilazolone is contraindicated. Furthermore, at least a two-week interval should be maintained between discontinuing an MAO inhibitor and initiating vilazolone, and vice versa. Linezolid is an anti-infective drug and a reversible MAO inhibitor. It is associated with multiple drug interactions and may cause serotonin syndrome, including some interactions associated with SSRIs. Given this potential risk, linezolid should generally not be used in patients receiving vilazolone. While the U.S. Food and Drug Administration (FDA) has not to date received any reports of serotonin syndrome resulting from the concomitant use of linezolid and vilazolone,… the risk of linezolid is considered comparable to that of selective serotonin reuptake inhibitors (SSRIs). However, the U.S. Food and Drug Administration (FDA) notes that certain life-threatening or emergency situations may require immediate treatment with linezolid in patients taking serotonergic drugs. In such emergencies, the availability of other anti-infective agents should be considered, and the benefits of linezolid should be weighed against the risks of serotonin syndrome. If linezolid is needed in such an emergency, verazordone must be discontinued immediately, and the patient should be monitored for central nervous system toxicity for 2 weeks or up to 24 hours after the last linezolid dose, whichever comes first. Verazordone can be resumed 24 hours after the last linezolid dose. If linezolid is planned for use in a non-emergency situation in a patient taking verazordone, verazordone should be discontinued for at least 2 weeks before starting linezolid. Verazordone should not be started in a patient taking linezolid; if necessary, verazordone may be used. Treatment should begin 24 hours after the last linezolid dose.

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Antidote and Emergency Treatment
/SRP:/ Immediate First Aid: Ensure adequate decontamination has been performed. If the patient stops breathing, begin artificial respiration immediately, preferably using a demand ventilator, bag-valve-mask, or simple breathing mask, following the training instructions. Perform cardiopulmonary resuscitation if necessary. Immediately flush contaminated eyes with running water. Do not induce vomiting. If vomiting occurs, tilt the patient forward or place them in the left lateral decubitus position (head down if possible) to maintain an open airway and prevent aspiration. Keep the patient calm and maintain normal body temperature. Seek medical assistance. /Class A and Class B Poisons/ Currance, PL Clements, B., Bronstein, AC (ed.); Emergency Care for Hazardous Substance Exposure. 3rd Edition, Revised, Elsevier Mosby, St. Louis, Missouri, 2007, p. 160
/SRP:/ Basic Treatment: Establish a patent airway (using an oropharyngeal or nasopharyngeal airway if necessary). Suction if necessary. Observe for signs of respiratory failure and provide assisted ventilation if necessary. Administer oxygen via a non-invasive mask at a flow rate of 10 to 15 liters per minute. Monitor for pulmonary edema and treat as necessary… Monitor for shock and treat as necessary… Anticipate seizures and treat as necessary… If eyes are contaminated, flush immediately with water. During transport, continuously flush each eye with 0.9% normal saline (NS)… Do not use emetics. If swallowed, rinse mouth and, if the patient is able to swallow, has a strong gag reflex, and does not drool, dilute with 5 mL/kg to 200 mL of water… After cleansing, cover skin burns with a dry, sterile dressing… /Type A and B Poisons/ Currance, PL Clements, B., Bronstein, AC (eds.); Emergency Care for Hazardous Substance Exposure. 3rd revised edition, Elsevier Mosby, St. Louis, Missouri, 2007, p. 160.
/SRP:/ Advanced Treatment: For patients with altered mental status, severe pulmonary edema, or severe respiratory distress, consider oropharyngeal or nasopharyngeal endotracheal intubation to control the airway. Positive pressure ventilation using a bag-valve-mask may be effective. Consider medical treatment for pulmonary edema… Consider the use of a beta-agonist (such as salbutamol) for severe bronchospasm… Monitor heart rhythm and treat arrhythmias as needed… Initiate intravenous infusion of 5% glucose solution (D5W TKO/SRP): Maintain patency of the IV line and administer as slowly as possible. If signs of hypovolemia appear, use 0.9% normal saline (NS) or lactated Ringer's solution (LR). Administer fluids with caution in cases of hypotension with signs of hypovolemia. Be alert for signs of fluid overdose… Use diazepam or lorazepam to treat seizures… Use promecaine hydrochloride to assist eye irrigation… /Poisons A and B/ Currance, PL Clements, B., Bronstein, AC (Eds).; Emergency Care for Hazardous Substance Exposure. 3rd Edition, Revised, Elsevier Mosby, St. Louis, Missouri, 2007, pp. 160-161.
There is currently no specific antidote for vilazolone. In case of overdose, supportive care should be provided, including close medical monitoring and surveillance. Treatment should include general measures for any drug overdose. Consider the possibility of multiple drug overdose. Ensure an open airway, adequate oxygenation, and normal ventilation. Monitor heart rhythm and vital signs. General supportive and symptomatic treatment is recommended. …The effectiveness of dialysis in removing vilazolone has not been studied; however, the large volume of distribution of vilazolone suggests that dialysis may not be effective in reducing its plasma concentration. National Institutes of Health; DailyMed. Latest medication information for virazolone (virazolone hydrochloride) tablets and virazolone (virazolone hydrochloride) kits (revised: July 2014). Available as of July 30, 2014, at: https://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=4c55ccfb-c4cf-11df-851a-0800200c9a66

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Special Risk Populations
Virazolone has not been systematically evaluated in patients with epilepsy; such patients have been excluded from clinical studies. As with other antidepressants, virazolone should be used with caution in patients with a history of epilepsy. American Association of Health System Pharmacists, 2014; Drug Information, 2014, Bethesda, MD, 2014, p. 2455.

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Protein binding rate: 96-99%.

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Acute in vivo toxicity: The LD50 of virazolone hydrochloride in male ICR mice (intraperitoneal injection) was 380 mg/kg. Mice at doses >250 mg/kg experienced transient ataxia and sedation, while those at doses ≤200 mg/kg did not die [3]
- Subacute toxicity: Rats were orally administered virazolone hydrochloride (10, 30, 100 mg/kg/day) for 28 days, and there were no significant changes in body weight (change <5%), serum ALT/AST/BUN/creatinine levels, or pathological damage to liver, kidney, or brain tissue [2]

[1]. CNS Neurosci Ther . 2009 Summer;15(2):107-17.

[2]. Eur J Pharmacol . 2005 Mar 7;510(1-2):49-57.

[3]. Eur J Pharmacol . 2004 Nov 3;504(1-2):65-77.

Vilazodone hydrochloride is a hydrochloride salt prepared by reacting vilazorone with an equivalent amount of hydrochloric acid. It is used to treat major depressive disorder. It has antidepressant, serotonin reuptake inhibitor, and serotonergic agonist effects. It contains a vilazorone (1+) group. Verazorone is a benzofuran, indole, and piperazine derivative that acts as a serotonin reuptake inhibitor and a partial serotonin 5-HT1 receptor agonist. It is used as an antidepressant. See also: Verazorone (containing the active moiety). Mechanism of Action: Verazordone hydrochloride (EMD 68843; SB659746A) exerts dual pharmacological effects: 1) inhibiting SERT to increase extracellular serotonin levels; 2) acting as a partial agonist of the 5-HT1A receptor, enhancing serotonergic transmission (presynaptic autoreceptor regulation + postsynaptic activation), thereby exerting antidepressant and anti-anxiety effects [2,3]. - Therapeutic Potential: Verazordone hydrochloride has been clinically approved for the treatment of major depressive disorder (MDD). Preclinical data show that it does not have sedative effects and does not impair cognitive function (unlike some SSRIs) [1,3]. - Chemical Properties: Verazordone hydrochloride (EMD 68843; SB659746A) is a white crystalline powder, soluble in water (15 mg/mL) and DMSO (45 mg/mL). At room temperature, it is stable for 72 hours in aqueous solutions with pH 4.0–7.0[2]

C26H28CLN5O2

477.99

477.193

C, 65.33; H, 5.90; Cl, 7.42; N, 14.65; O, 6.69

163521-08-2

Vilazodone-d8; 1794789-93-7; Vilazodone; 163521-12-8; Vilazodone carboxylic acid; 163521-19-5

6918313

White to yellow solid powder

745.1ºC at 760 mmHg

279°C(lit.)

404.4ºC

5.718

3

5

7

34

729

0

Cl[H].O1C(C(N([H])[H])=O)=C([H])C2=C1C([H])=C([H])C(=C2[H])N1C([H])([H])C([H])([H])N(C([H])([H])C([H])([H])C([H])([H])C([H])([H])C2=C([H])N([H])C3C([H])=C([H])C(C#N)=C([H])C2=3)C([H])([H])C1([H])[H]

RPZBRGFNBNQSOP-UHFFFAOYSA-N

InChI=1S/C26H27N5O2.ClH/c27-16-18-4-6-23-22(13-18)19(17-29-23)3-1-2-8-30-9-11-31(12-10-30)21-5-7-24-20(14-21)15-25(33-24)26(28)32;/h4-7,13-15,17,29H,1-3,8-12H2,(H2,28,32);1H

5-[4-[4-(5-cyano-1H-indol-3-yl)butyl]piperazin-1-yl]-1-benzofuran-2-carboxamide;hydrochloride

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 (5.23 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 (5.23 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 (5.23 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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 (Please use freshly prepared in vivo formulations for optimal results.)