5-HT_1A Receptor
Vilazodone has an IC50 of 0.5 nM for the SERT and 0.2 nM at the human 5-HT₁A receptor. Vilazodone exhibits high affinity (pKi≥9.3) for human recombinant and native tissue 5-HT₁A receptors from rats, mice, marmosets, and guinea pigs, and it preferentially binds to the high agonist affinity state of human 5-HT₁A receptors. Vilazodone functions at 5-HT₁A receptors as a partial agonist with high efficacy. A single concentration of Vilazodone (100nM) increases basal binding by approximately 70% of that produced by the full 5-HT₁A receptor agonist, 8‐OH‐PIPAT, in [³⁵S]GTPγS binding studies in Sf9 cells expressing h5-HT₁A receptors. Vilazodone exhibits potent partial agonistic effects on the 5‐HT1A receptor, as demonstrated by [³⁵S]GTPγS binding studies conducted in rat hippocampal membranes. Its intrinsic activity is 0.61 and its pEC50 is 8.1. Vilazodone has a potent inhibitory effect on 5‐HT reuptake in the cortex of rats and guinea pigs. Vilazodone has an 8.8 pIC50 to inhibit [3H]5-HT uptake in LLCPK cells that express human SERT[1].

Vilazodone has an IC50 of 0.5 nM for the SERT and 0.2 nM at the human 5-HT₁A receptor. Vilazodone exhibits high affinity (pKi≥9.3) for human recombinant and native tissue 5-HT₁A receptors from rats, mice, marmosets, and guinea pigs, and it preferentially binds to the high agonist affinity state of human 5-HT₁A receptors. Vilazodone functions at 5-HT₁A receptors as a partial agonist with high efficacy. A single concentration of Vilazodone (100nM) increases basal binding by approximately 70% of that produced by the full 5-HT₁A receptor agonist, 8‐OH‐PIPAT, in [³⁵S]GTPγS binding studies in Sf9 cells expressing h5-HT₁A receptors. Vilazodone exhibits potent partial agonistic effects on the 5‐HT1A receptor, as demonstrated by [³⁵S]GTPγS binding studies conducted in rat hippocampal membranes. Its intrinsic activity is 0.61 and its pEC50 is 8.1. Vilazodone has a potent inhibitory effect on 5‐HT reuptake in the cortex of rats and guinea pigs. Vilazodone has an 8.8 pIC50 to inhibit [3H]5-HT uptake in LLCPK cells that express human SERT[1].

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Vilazodone acts as a high-efficacy partial agonist at human recombinant and native tissue 5-HT₁ₐ receptors, with pKᵢ values ≥ 9.3 against [³H]8-OH-DPAT.
It displays a 2 log unit lower affinity for the antagonist radioligand [³H]WAY100635, indicating preferential binding to the high agonist affinity state of 5-HT₁ₐ receptors.
In [³⁵S]GTPγS binding assays using HEK cells expressing human 5-HT₁ₐ receptors, vilazodone acts as a full agonist with a pEC₅₀ of 9.0.
In rat hippocampal membranes, vilazodone acts as a potent partial agonist with a pEC₅₀ of 8.1 and an intrinsic activity of 0.61.
Vilazodone inhibits [³H]5-HT uptake into LLCPK cells expressing human SERT with a pIC₅₀ of 8.8 ± 0.05. [1]

Vilazodone (intraperitoneal injection; 3 mg/kg ; single dose) causes increases in extracellular 5‐HT in rat frontal cortex (FC) and ventral hippocampal (vHipp) in in vivo microdialysis studies. Maximum increases are seen at 3 mg/kg, where they reach, in the FC and vHipp, 527% and 558% of preinjection baseline values, respectively[2]. Vilazodone (55 mg/kg; single dose; oral gavage) inhibits vocalizations induced by stress in the rat ultrasonic vocalizations test 120 and 210 minutes after the dose[2].

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In rat frontal cortex and ventral hippocampus, vilazodone (3 mg/kg ip) increased extracellular 5-HT levels to 527% and 558% of baseline, respectively.
Unlike fluoxetine, vilazodone-induced 5-HT increases were only partially reversed by 8-OH-DPAT.
Vilazodone did not induce 5-HT syndrome behaviors or decrease body temperature in rats, unlike 8-OH-DPAT.
In rat anxiety models, vilazodone showed anxiolytic efficacy in ultrasonic vocalization and shock-probe burying tests, but not in the elevated plus maze.
In the forced swim test, vilazodone reduced immobility time at 1 mg/kg ip in rats and mice. [1]

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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\n\n In comparison, the 5-HT1A/B/D receptor partial agonist SB-272183 ((5-Chloro-2, 3-dihydro-6-[4-methylpiperazin-1-yl]-1[4-pyridin-4-yl]napth-1-ylaminocarbonyl]-1H-indole), which has been reported to act as a 5-HT1A receptor antagonist at rodent and human native tissue 5-HT1A receptors, displayed an intrinsic activity of approximately 0.3 in the same study (Fig. 2). Interestingly, in [35S]GTPγS binding studies in rat hippocampal membranes (a functional preparation in which 5-HT1A receptors predominate), vilazodone acted as a potent 5-HT1A receptor partial agonist with a pEC50 of 8.1 and an intrinsic activity of 0.61. In comparison, (±) 8-OH-DPAT (pEC50 7.2) produced a partial agonist response with an intrinsic activity of 0.45 and the partial agonist buspirone showed a pEC50= 6.5 ± 0.35 and an intrinsic activity of 0.19. Taken together, these data suggest that vilazodone would be a high efficacy 5-HT1A receptor partial agonist, in vivo. The apparent difference in intrinsic activities between recombinant and native tissue systems may be a consequence of varying degrees of receptor reserve. Indeed, receptor reserve has been reported to be present for native tissue somatodendritic 5-HT1A autoreceptors in vivo[49] but not native postsynaptic 5-HT1A receptors in vitro, which would explain why vilazodone demonstrated partial agonist properties in the hippocampus. Therefore, one possible conclusion is that vilazodone is a 5-HT1A receptor partial agonist with the potential to act as a full agonist in systems with high receptor reserve and/or improved receptor–G protein coupling efficiency. This concept is supported by the observation that vilazodone appeared to have much higher efficacy at pre- versus postsynaptic 5-HT1A receptors in some in vivo models but is perhaps contradicted by some of the neurochemical observations.[1]

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\n\nCombinations of biochemical and electrophysiological studies have demonstrated that vilazodone acts as a potent 5-HT reuptake inhibitor in rat and guinea pig cortex. We have confirmed this high potency in LLCPK cells expressing human SERT, whereby vilazodone inhibited [3H]5-HT uptake with a pIC50 of 8.8 ± 0.05 (Fig. 3). This potency value is approximately 1 log unit greater than that for fluoxetine but similar to that for paroxetine (unpublished observations). These data, taken together with the observation that vilazodone is a potent 5-HT1A receptor partial agonist, puts this molecule in a novel class of compound that has the potential to rapidly desensitize 5-HT1A autoreceptors both directly, via 5-HT1A receptor agonism, and indirectly, via elevations in endogenous 5-HT through SERT inhibition.[1]

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Receptor binding studies were performed using the agonist radioligand [³H]8-OH-DPAT and the antagonist radioligand [³H]WAY100635 in the presence of Gpp(NH)p to assess affinity for 5-HT₁ₐ receptors in human recombinant and native tissue preparations.
[³⁵S]GTPγS binding assays were conducted in HEK cells expressing human 5-HT₁ₐ receptors and rat hippocampal membranes to determine functional agonist activity and intrinsic activity of vilazodone. [1]

[³H]5-HT uptake inhibition assays were performed in LLCPK cells expressing human recombinant SERT to evaluate vilazodone’s potency as a serotonin reuptake inhibitor. [1]

Efficacy in Models of Anxiety[1]
Three separate studies have evaluated the efficacy of vilazodone in various rodent models thought to be predictive of anxiolytic activity. In the rat ultrasonic vocalizations test, stress-induced vocalizations were inhibited by vilazodone (55 mg/kg po) at 120 and 210 min post dose. In comparison, 8-OH-DPAT (0.55 mg/kg sc) produced a similar, but shorter duration, activity that was reversed by WAY 100635. In contrast, the SSRI fluoxetine (100 mg/kg po) was without effect unless combined with 8-OH-DPAT. Together these data suggest that the vilazodone-mediated efficacy in this model was via its 5-HT1A receptor agonist activity. In two further rat models of anxiety, that is, the elevated plus maze and the shock-probe burying tests, vilazodone demonstrated dose related efficacy (10–40 mg/kg ip) in the shock probe test but, interestingly, was without effect in the elevated plus maze. The positive control diazepam produced efficacy in both paradigms. Finally, vilazodone was examined in a predator-induced stress paradigm, brought about by unprotected exposure to a domestic cat. Predator stress increased anxiety-like behaviors in the elevated plus maze and an increased response to an acoustic startle. Vilazodone (20–40 mg/kg ip), administered acutely or prophylactically (1 week prior to behavioral testing), attenuated stress-induced potentiated startle but had no effect on stress potentiated anxiety response in the elevated plus maze. Interestingly, a lower dose of 10 mg/kg of vilazodone had the opposite effect in the startle response, indicating a somewhat unexplained bidirectional effect, and all doses produced a potentiation of the startle-induced stress response possibly suggestive of an anxiogenic-like response. Finally, the data from these studies also showed that vilazodone had neither sedation nor stimulatory effects but did produce context-dependent efficacy.

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Efficacy in Models of Antidepressant Activity[1]
The FST is widely used to assess the potential of molecules to exhibit an antidepressant profile since all major classes of antidepressant drugs, including tricyclic antidepressants (TCA), SNRI and SSRI, monoamine oxidase inhibitors, and atypical ADs [70–74], are effective in this stress based model. Page et al.demonstrated that vilazodone produced efficacy (i.e., a reduction in immobility time) in both the rat and mouse versions of this model at a single dose (1 mg/kg ip), whilst higher doses (3 and 10 mg/kg) were without effect. The magnitude of this efficacy was approximately similar to that of fluoxetine. Efficacy in this model is generally considered to be mediated by 5-HT and blocked by receptor antagonists and genetic deletions of 5-HT1A receptors. Thus vilazodone-mediated efficacy may be via direct 5-HT1A receptor agonism or alternatively indirect through elevations in endogenous 5-HT. Perhaps the major driving force behind this mechanistic combination of these two activities is a hastened desensitization of 5-HT1A receptors leading to an enhanced onset of therapeutic activity. Therefore some evaluation of the onset of preclinical efficacy in models thought to mimic this, such as rodent social interaction or schedule induced polydipsia, would be useful but unfortunately has not been reported to date.

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Microdialysis studies in rats: vilazodone was administered intraperitoneally (3 mg/kg) or orally (1–10 mg/kg) to measure extracellular 5-HT levels in frontal cortex and ventral hippocampus.
Behavioral tests: vilazodone was administered intraperitoneally (1–10 mg/kg) or orally (up to 55 mg/kg) in ultrasonic vocalization, elevated plus maze, shock-probe burying, predator stress, and forced swim tests.
Body temperature measurement: vilazodone (55 mg/kg po) was administered to rats, and body temperature was recorded. [1]

Absorption, Distribution and Excretion
The bioavailability of vilazolone when taken with food is 72%. 1% of the dose is excreted unchanged in the urine, and 2% is excreted unchanged in the feces. The volume of distribution of vilazolone is unknown, but is relatively large. The clearance of vilazolone in patients with mild to moderate renal impairment is 19.9–25.1 L/h, compared to 26.4–26.9 L/h in healthy controls. Peak plasma concentrations of vilazolone are reached 4–5 hours after administration (Tmax) and decline over a terminal half-life of approximately 25 hours. The absolute bioavailability of vilazolone when taken with food is 72%. Taking VIIBRYD with food (high-fat or low-fat meals) increases oral bioavailability (Cmax increases by approximately 147–160%, AUC increases by approximately 64–85%).
Verazolide is widely distributed, with a protein binding rate of approximately 96-99%.
Verazolide is secreted into the milk of lactating rats.
Metabolism/Metabolites
Verazolide is primarily metabolized via cytochrome P450 (CYP) 3A4, with smaller amounts metabolized via CYP2C19 and CYP2D6. Although the metabolic pathways of virazolone are not fully understood, a hypothetical metabolic mechanism in rats was published in 2017.
Verazolide is primarily metabolized via CYP and non-CYP pathways (possibly via carboxylesterases), with only 1% of the dose excreted unchanged in the urine and 2% excreted in the feces. Within the CYP pathway, CYP3A4 is the dominant metabolic pathway, while CYP2C19 and CYP2D6 contribute less. In vitro studies using human microsomes and human hepatocytes suggest that vilazolone is unlikely to inhibit or induce the metabolism of other CYP substrates (except CYP2C8); in vivo studies using CYP2C19, 2D6, and 3A4 probe substrates have shown that vilazolone does not alter the pharmacokinetics of these probe substrates. However, an in vivo study using the CYP2C19 probe substrate indicated weak induction by CYP2C19. Potent CYP3A4 inhibitors (e.g., ketoconazole) reduce the metabolism of vilazolone in vivo, thereby increasing its exposure. Conversely, potent CYP3A4 inducers (e.g., carbamazepine) reduce vilazolone exposure.

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Biological half-life
25 hours. Other studies have shown that after a single 40 mg dose, the half-life of vilazolone is 24 ± 5.2 hours; after repeated dosing, the half-life is 28.9 ± 3.2 hours.
The terminal half-life of virazolone is approximately 25 hours. Virazolone is metabolized to 6-hydroxy-5-cyanoindole and excreted as glucuronide. In a PET study using [¹¹C]WAY100635, virazolone (40 mg) preferentially occupied presynaptic 5-HT₁ₐ receptors in healthy subjects when plasma concentrations were >50 ng/mL. [1]

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. At lower doses, early postnatal mortality in pups increased, surviving pups had lower body weight, delayed maturation, and decreased adult fertility. Some maternal toxicity exists at this dose.

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Drug Interactions
Vapazolone concomitant use with intermediate-acting CYP3A4 inhibitors (such as erythromycin) can lead to elevated plasma virazolone concentrations. If intolerable adverse reactions occur when used concomitantly with intermediate-acting CYP3A4 inhibitors (such as erythromycin), the virazolone dose should be reduced to 20 mg once daily.
Vapazolone concomitant use with potent CYP3A4 inhibitors (such as clarithromycin and ketoconazole) can increase plasma virazolone concentrations by approximately 50%. The manufacturer states that if a potent CYP3A4 inhibitor is taken concurrently, the virazolone dose should be reduced to 20 mg once daily. Concomitant use with potent CYP3A4 inhibitors may result in potentially serious adverse reactions, sometimes even fatal. Patients currently receiving or recently receiving monoamine oxidase (MAO) inhibitors may experience such adverse reactions if they subsequently start using an antidepressant with similar pharmacological effects to vilazolone (e.g., selective serotonin reuptake inhibitors, SSRIs), or if they received SSRI treatment shortly before starting an MAO inhibitor. Concomitant use of MAO inhibitors with vilazolone is contraindicated. Furthermore, at least a two-week interval should be maintained between discontinuing an MAO inhibitor and starting 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. To date, the U.S. Food and Drug Administration (FDA) has not received any reports of serotonin syndrome caused by the concomitant use of linezolid and vilazolone; the risk is considered comparable to that of selective serotonin reuptake inhibitors (SSRIs). However, the FDA notes that in certain life-threatening or emergency situations, patients taking serotonergic drugs may require immediate treatment with linezolid. In such emergencies, the availability of other anti-infective drugs 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 symptoms for 2 weeks or up to 24 hours after the last dose of linezolid, whichever comes first. Verazordone can be resumed 24 hours after the last dose of linezolid. If linezolid is planned for use in a non-emergency situation in a patient taking verazordone, verazordone should be discontinued at least 2 weeks before starting linezolid. Patients currently receiving linezolid should not start verazordone; if necessary, verazordone can be started 24 hours after the last dose of linezolid.
For more complete data on drug interactions of virazolone (13 in total), please visit the HSDB record page.

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Virazolone was generally well tolerated in clinical trials. Common adverse reactions included diarrhea, nausea, somnolence, and dizziness. [1]

[1]. Vilazodone: A 5-HT1A Receptor Agonist/Serotonin Transporter Inhibitor for the Treatment of Affective Disorders CNS Neuroscience & Therapeutics Volume 15, Issue 2, pages 107-117, June 2009

[2]. Vilazodone HCl (Viibryd): A Serotonin Partial Agonist and Reuptake Inhibitor For the Treatment of Major Depressive Disorder. P T. 2012 Jan;37(1):28-31.

Therapeutic Uses

Antidepressant
Viibryd is indicated for the treatment of major depressive disorder (MDD). The efficacy of Viibryd has been demonstrated in two 8-week randomized, double-blind, placebo-controlled trials in adult patients diagnosed with MDD. Major depressive disorder consists of one or more major depressive episodes. A major depressive episode (DSM-IV-TR) is defined as a significant and relatively persistent (at least 2 weeks, occurring almost daily) depressed or irritable mood that typically interferes with daily functioning and includes at least 5 of the following 9 symptoms: depressed mood, loss of interest in daily activities, significant changes in weight and/or appetite, insomnia or somnolence, psychomotor agitation or retardation, increased fatigue, feelings of guilt or worthlessness, slowed thinking or difficulty concentrating, or suicidal attempt or ideation. /US product label includes/
Explore Treatment Sexual dysfunction is common in major depressive disorder (MDD), and many serotonergic antidepressants can have adverse effects on sexual function. Verazordone is a novel serotonin (5-HT) reuptake inhibitor and 5-HT1A partial agonist approved for the treatment of MDD. It acts on 5-HT transporters and presynaptic and postsynaptic 5-HT1A receptors. This mechanism may help alleviate sexual dysfunction. Objective: To summarize the effects of vilazordone (40 mg/day, taken with food) on sexual function in adult patients with MDD. /Data from/ Three Phase III studies: two 8-week placebo-controlled studies and one 52-week open-label study. Validated measures were used to assess changes in sexual function from baseline to the end of treatment (EOT). The study population included 869 patients from the placebo-controlled studies (436 in the vilazordone group and 433 in the placebo group) and 599 patients from the open-label study. The prevalence of sexual dysfunction was high (50% in men and 68% in women) before treatment. The incidence of sexual dysfunction decreased in both the vilazolone and placebo groups during treatment, indicating improvement on average. At the end of treatment, ≥91% of patients in the placebo-controlled study had stable or improved sexual function; there was no statistically significant difference in sexual dysfunction between the two groups at the end of treatment. Changes in sexual function scores from baseline were smaller and generally not statistically significant compared to the placebo group; the effect size (Cohen's d) was generally lower. In the placebo-controlled study, 8.0% of patients treated with vilazolone and 0.9% of patients treated with placebo reported ≥1 sexual function-related adverse event during treatment (P<0.001). At baseline, half of the men and two-thirds of the women with major depressive disorder had sexual dysfunction; sexual function improved on average in both the vilazolone and placebo groups. These results suggest that vilazolone may have a smaller adverse effect on sexual function relative to the high prevalence of sexual dysfunction in adults with major depressive disorder at baseline.

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Medication Warning
/Black Box Warning/ Warning: Suicidal Ideation and Behavior. 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 aged 24 years and older; the risk was reduced in patients aged 65 years and older. Patients of all ages starting antidepressant treatment should be closely monitored for worsening clinical symptoms and the occurrence of suicidal ideation and behavior. Inform family members and caregivers of the need for close monitoring and communication with the prescribing physician. Viibryd is not approved for use in children.
Adults and children with major depressive disorder or other mental illness may experience worsening of depressive symptoms and/or suicidal ideation and behavior (suicidal tendencies) or abnormal behavioral changes, regardless of whether they are taking antidepressants. This risk may persist until clinical symptoms are significantly relieved. Suicide is a known risk factor for depression and certain other mental illnesses, which are themselves the strongest predictors of suicide. However, there has long been concern that antidepressants may induce exacerbations of depressive symptoms and suicidal tendencies in some patients during the early stages of treatment. A meta-analysis of short-term placebo-controlled studies of antidepressants (e.g., selective serotonin reuptake inhibitors (SSRIs) and other antidepressants) showed an increased risk of suicide in children, adolescents, and young adults (18–24 years) with major depressive disorder and other mental illnesses. In adults over 24 years of age, antidepressants did not show an increased risk of suicide compared to placebo, while a decreased risk was observed in adults 65 years of age and older. The U.S. Food and Drug Administration (FDA) recommends that all patients receiving antidepressant treatment, regardless of their indication, should be appropriately monitored for worsening clinical symptoms, suicidal tendencies, and abnormal behavioral changes, especially during the initial stages of treatment (i.e., the first few months) and during dose adjustments. For patients with major depressive disorder or other mental or non-mental illnesses receiving antidepressant treatment, family members and caregivers should be advised to monitor the patient daily for agitation, irritability, or abnormal behavioral changes, as well as suicidal tendencies, and to report such symptoms to healthcare professionals immediately. Although a causal relationship has not been established between symptoms such as anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggression, impulsivity, akathisia, hypomania, and/or mania and the exacerbation of depression and/or the onset of suicidal ideation, there are concerns that these symptoms may be precursors to suicidal tendencies. Therefore, for patients with persistently worsening depressive symptoms, or those experiencing sudden suicidal ideation or symptoms that may foreshadow worsening depressive symptoms or suicidal tendencies, a change in treatment plan or discontinuation of treatment should be considered, especially if these symptoms are severe, sudden in onset, or not the primary symptoms present at the time of consultation. If the decision is made to discontinue treatment, the dose of vilazolone should be reduced as quickly as possible, while also considering the risks of abrupt discontinuation. The FDA also recommends that these medications be prescribed at the lowest possible dose while ensuring good patient management to reduce the risk of overdose.
It has been reported that the use of antidepressants alone may cause life-threatening serotonin syndrome or neuroleptic malignant syndrome (NMS)-like reactions, especially when used concurrently with other serotonergic drugs (including serotonin (5-HT) type 1 receptor agonists (triptans)), drugs that impair serotonin metabolism (e.g., monoamine oxidase inhibitors), or antipsychotics or other dopamine antagonists. Clinical manifestations of serotonin syndrome may include altered mental status (e.g., agitation, hallucinations, coma), autonomic dysfunction (e.g., tachycardia, blood pressure fluctuations, hyperthermia), neuromuscular abnormalities (e.g., hyperreflexia, incoordination), and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). In the most severe cases, serotonin syndrome may resemble neuroleptic malignant syndrome (NMS), characterized by hyperthermia, muscle rigidity, autonomic dysfunction (possibly accompanied by rapid fluctuations in vital signs), and altered mental status. Patients taking verazorazolone should be monitored for the occurrence of serotonin syndrome or NMS-like signs and symptoms. Concomitant or recent (i.e., within 2 weeks) use of monoamine oxidase inhibitors (MAO inhibitors) for the treatment of depression is prohibited. If clinical necessity necessitates the concurrent use of vilazolone and a 5-HT1 receptor agonist (triptan), the patient should be closely monitored, especially at the beginning of treatment, at dose increases, or when starting other serotonergic medications. Concomitant use of vilazolone and serotonin precursors (e.g., tryptophan) is not recommended. If signs and symptoms of serotonin syndrome or neuroleptic malignancy (NMS) occur, vilazolone and any concurrently used serotonergic or antidopaminergic medications (including antipsychotics) should be immediately discontinued, and supportive and symptomatic treatment should be initiated. Infants exposed to selective serotonin reuptake inhibitors (SSRIs) during pregnancy may have an increased risk of persistent pulmonary hypertension (PPHN) in the newborn. The incidence of PPHN in the general population is 1–2 per 1000 live births and is significantly associated with neonatal morbidity and mortality. Several recent epidemiological studies have shown a statistically positive correlation between the use of selective serotonin reuptake inhibitors (SSRIs) (including veblimited) during pregnancy and PPHN. Other studies have not found a significant statistical correlation. For more complete data on drug warnings for vilazolone (16 in total), please visit the HSDB records page. Pharmacodynamics: Viprazole increases serotonin levels in the brain by inhibiting serotonin reuptake and acting as a partial agonist of the serotonin-1A receptor. Due to this activity, vilazolone is sometimes referred to as a selective partial agonist and reuptake inhibitor (SPARI). Viprazole is a drug that combines a serotonin reuptake inhibitor and a 5-HT₁ₐ receptor partial agonist, designed to accelerate the onset of action of antidepressants by desensitizing the 5-HT₁ₐ autoreceptors in cell somatic dendrites. It has entered a phase III clinical trial for the treatment of major depressive disorder and has shown significantly better efficacy than placebo on the Montgomery-Osberg Depression Rating Scale (MADRS). The drug was originally developed by Merck KGaA and later licensed to GlaxoSmithKline (GSK) and Clinical Data. [1]

C₂₆H₂₇N₅O₂

441.52

441.22

163521-12-8

Vilazodone Hydrochloride; 163521-08-2; Vilazodone-d8; 1794789-93-7; Vilazodone carboxylic acid; 163521-19-5

6918314

White to light yellow solid powder

1.34 g/cm3

745.1ºC at 760 mmHg

203-205ºC

5.534

2

5

7

33

729

0

SGEGOXDYSFKCPT-UHFFFAOYSA-N

InChI=1S/C26H27N5O2/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)

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

EMD 68843; SB659746A; 5-(4-(4-(5-Cyano-1H-indol-3-yl)butyl)piperazin-1-yl)benzofuran-2-carboxamide; Viibryd; EMD 515259; vilazodona; vilazodonum; UNII-S239O2OOV3; Vilazodone; EMD68843; EMD-68843

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

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

DMSO: 75~88 mg/mL (199.3~169.9 mM)
Ethanol: ~14 mg/mL

Solubility in Formulation 1: ≥ 2.5 mg/mL (5.66 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 (5.66 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.)