to its clinical antidepressant efficacy is unclear. ssris and 5-ht1a receptor agonists often produce nausea as a side effect, whereas 5-ht3 receptor antagonists like ondansetron are antiemetics and have been found to be effective in treating ssri-induced nausea. it was thought that the 5-ht3 receptor antagonism of vortioxetine would reduce the incidence of nausea relative to ssris. however, clinical trials found significant and dose-dependent rates of nausea with vortioxetine that appeared to be comparable to those found with the snri duloxetine. pharmacokinetics vortioxetine levels after a single 10 mg oral dose of vortioxetine in 18 fasted and 18 fed healthy japanese adults. simulation of vortioxetine levels and accumulation with 10 mg/day oral vortioxetine plus a 17 mg intravenous bolus of vortioxetine versus 10 mg/day oral vortioxetine alone. vortioxetine is well-absorbed when taken orally and has an oral bioavailability of 75%. it is systemically detectable after a single oral dose by 0.781 hours. peak levels of vortioxetine are reached within 7 to 11 hours post-dose with single or multiple doses. steady-state levels of vortioxetine are generally reached within 2 weeks of administration, with 90% of individuals reaching 90% of steady state after 12 days of administration. steady-state peak levels of vortioxetine with doses of 5, 10, and 20 mg/day were 9, 18, and 33 ng/ml, respectively. the accumulation index of vortioxetine (area-under-the-curve levels after a single dose versus at steady state) is 5 to 6. a loading dose given intravenously has been found to achieve steady-state levels more rapidly with oral vortioxetine therapy. the pharmacokinetics of vortioxetine are known to be linear and dose proportional over a range of 2.5 to 75 mg for single doses and 2.5 to 60 mg for multiple doses. food has no influence on the pharmacokinetics of vortioxetine. the apparent volume of distribution of vortioxetine is large and ranges from 2,500 to 3,400 l after single or multiple doses of 5 to 20 mg vortioxetine, with extensive extravascular distribution. the plasma protein binding of vortioxetine is approximately 98 or 99%, with about 1.25 ± 0.48% free or unbound. vortioxetine is extensively metabolized by oxidation via cytochrome p450 enzymes and subsequent glucuronidation via udp-glucuronosyltransferase. cyp2d6 is the primary enzyme involved in the metabolism of vortioxetine, but others including cyp2a6, cyp2b6, cyp2c8, cyp2c9, cyp2c19, and cyp3a4/5 are also involved. it is also metabolized by alcohol dehydrogenase, aldehyde dehydrogenase, and aldehyde oxidase. six metabolites of vortioxetine have been identified. the major metabolite of vortioxetine (lu aa34443) is inactive and its minor active metabolite (lu aa39835) is not thought to cross the blood–brain barrier. the remaining metabolites are glucuronide conjugates. hence, vortioxetine itself is thought to be primarily responsible for its pharmacological activity. the estimated total clearance of vortioxetine ranges from 30 to 41 l/h. the elimination half-life of vortioxetine is 66 hours, with a range of 59 to 69 hours after single or multiple doses. elimination of vortioxetine is almost entirely via the liver (99%) rather than the kidneys (<1%). approximately 85% of vortioxetine was recovered in a single-dose excretion study after 15 days, with 59% in urine and 26% in feces. pharmacogenomics genetic variations in cytochrome p450 enzymes can influence exposure to vortioxetine. cyp2d6 extensive metabolizers have approximately 2-fold higher clearance of vortioxetine than cyp2d6 poor metabolizers. the estimated clearance rates were 52.9, 34.1, 26.6, and 18.1 l/h for cyp2d6 ultra-rapid metabolizers, extensive metabolizers, intermediate metabolizers, and poor metabolizers. area-under-the-curve levels of vortioxetine were 35.5% lower in cyp2d6 ultra-rapid metabolizers than in extensive metabolizers, though with significant overlap due to interindividual variability. dosage adjustment for cyp2d6 ultra-rapid metabolizers is considered to not be necessary. vortioxetine exposure in cyp2d6 poor metabolizers is expected to be approximately twice as high as in extensive metabolizers. depending on the individual response, dosage adjustment may be considered for cyp2d6 poor metabolizers, with a maximum recommended dosage of 10 mg/day for known such individuals. in addition to cyp2d6, cyp2c19 extensive metabolizers have 1.4-fold higher clearance of vortioxetine than poor metabolizers. however, this is not considered to be clinically important and dose adjustment is not considered to be necessary based on cyp2c19 status. chemistry vortioxetine (1-piperazine) is a bis-aryl-sulfanyl amine as well as piperazine derivative. the acid dissociation constant (pka) values for vortioxetine hydrobromide were determined to be 9.1 (± 0.1) and 3.0 (± 0.2) according to an australian public assessment report. history vortioxetine 10 mg tablets (trintellix). vortioxetine was discovered by scientists at lundbeck who reported the rationale and synthesis for the drug (then called lu aa21004) in a 2011 paper. in 2007, the compound was in phase ii clinical trials, and lundbeck and takeda entered into a partnership in which takeda paid lundbeck $40 million up-front, with promises of up to $345 million in milestone payments, and takeda agreed to pay most of the remaining cost of developing the drug. the companies agreed to co-promote the drug in the us and japan, and that lundbeck would receive a royalty on all such sales. the deal included another drug candidate, tedatioxetine (lu aa24530), and could be expanded to include two other lundbeck compounds. vortioxetine was approved by the u.s. food and drug administration (fda) for the treatment of major depressive disorder (mdd) in adults in september 2013, and it was approved in the european union later that year. society and culture it is made by the pharmaceutical companies lundbeck and takeda. names vortioxetine was previously sold under the brand name brintellix in the united states, but in may 2016, the us food and drug administration (fda) approved a name change to trintellix in order to avoid confusion with the blood-thinning medication brilinta (ticagrelor). in india, it is sold under the name vantaxa. research vortioxetine was under development for the treatment of generalized anxiety disorder and attention-deficit hyperactivity disorder (adhd) but development for these indications was discontinued. as of august 2021, vortioxetine remains in development for the treatment of anxiety disorders, binge-eating disorder, and bipolar disorder. it is in phase ii clinical trials for these indications. there is also interest in vortioxetine for the potential treatment of social phobia, neuropathic pain, and for cognitive enhancement in major depression.