vortioxetine vortioxetine vortioxetine, sold under the brand names trintellix and brintellix among others, is a medication used to treat major depressive disorder. effectiveness is viewed as similar to that of other antidepressants. it is taken by mouth. vortioxetineclinical datapronunciation/vɔːrtiˈɒksətiːn/ vor-tee-ok-sə-teen trade namestrintellix, brintellix, othersother nameslu aa21004, vortioxetine hydrobromide (jan jp), vortioxetine hydrobromide (usan us)ahfs/drugs.commonographmedlineplusa614003license data eu ema: by inn us dailymed: vortioxetine us fda: vortioxetine pregnancycategory au: b3 routes ofadministrationby mouthatc coden06ax26 (who) legal statuslegal status au: s4 (prescription only) uk: pom (prescription only) us: ℞-only eu: rx-only in general: ℞ (prescription only) pharmacokinetic databioavailability75% (peak at 7–11 hours)protein binding98–99%metabolismliver, primarily cyp2d6-mediated oxidationelimination half-life66 hoursexcretion59% in urine, 26% in fecesidentifiers iupac name 1-piperazine cas number508233-74-7 ypubchem cid9966051iuphar/bps7351drugbankdb09068 ychemspider8141643 yunii3o2k1s3wqvas salt: tks641koaykeggd10184 yas salt: d10185 ychebichebi:76016 ychemblchembl2204360 ycomptox dashboard (epa)dtxsid80965062 echa infocard100.258.748 chemical and physical dataformulac18h22n2smolar mass298.45 g·mol−13d model (jsmol)interactive image smiles cc(c=c(c)c=c1)=c1sc2=c(n3ccncc3)c=cc=c2 inchi 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 nkey:yqnwzwmkldqsac-uhfffaoysa-n n (verify) common side effects include nausea, vomiting, constipation, and sexual dysfunction. serious side effects may include suicide in those under the age of 25, serotonin syndrome, bleeding, mania, and siadh. a withdrawal syndrome may occur if the medication is abruptly stopped or the dose is decreased. use during pregnancy and breastfeeding is not generally recommended. it is classified as a serotonin modulator and stimulator. how it works is not entirely clear but is believed to be related to increasing serotonin levels and possibly interacting with certain receptors for serotonin. it was approved for medical use in the united states in 2013. in 2020, it was the 243rd most commonly prescribed medication in the united states, with more than 1 million prescriptions. medical uses vortioxetine is used as a treatment for major depressive disorder. effectiveness appears to be similar to other antidepressants and in terms of effect size has been described as modest. vortioxetine may be used when other treatments have failed. a 2017 cochrane review on vortioxetine determined that the place for it in the treatment of severe depression is unclear due to low-quality evidence and that more study is needed comparing vortioxetine to selective serotonin reuptake inhibitors (ssris) which are typical first-line treatments. vortioxetine is also used off-label for anxiety. a 2016 review found it was not useful in generalized anxiety disorder at 2.5, 5, and 10 mg doses (15 and 20 mg doses were not tested). a 2019 meta-analysis found that vortioxetine did not produce statistically significant results over placebo in the symptoms, quality of life and remission rates of generalized anxiety disorder, but it was well-tolerated. however, a 2018 meta-analysis supported use and efficacy of vortioxetine for generalized anxiety disorder, though stated that more research was necessary to strengthen the evidence. a 2021 systematic review and meta-analysis concluded that there was uncertainty about the effectiveness of vortioxetine for anxiety due to existing evidence being very low-quality. in a 2020 network meta-analysis of randomized controlled trials, vortioxetine was associated with among the lowest remission rates for generalized anxiety disorder of the included medications (odds ratio = 1.30 for vortioxetine, range of odds ratios for other agents = 1.13–2.70). effectiveness of vortioxetine at 10, 15, and 20 mg/day versus placebo and duloxetine at 60 mg/day in the treatment of major depressive disorder in adults over 8 weeks (measured by improvement on the montgomery–åsberg depression rating scale) in two randomized controlled trials. changes in madrs total score from baseline at week 8 were –10.8 to –12.8 for placebo, –13.0 to –15.6 for vortioxetine, and –16.9 for duloxetine. contraindications vortioxetine is contraindicated in those taking monoamine oxidase inhibitors (maois) due to the possibility of serotonin syndrome. adverse effects side effects of vortioxetine at different doses in clinical trials side effect placebo vortioxetine duloxetine 5 mg/day 10 mg/day 15 mg/day 20 mg/day 60 mg/day any 62% 66% 67% 70% 73% 77% nausea 9% 21% 26% 32% 32% 36% vomiting 1% 3% 5% 6% 6% 4% diarrhea 6% 7% 7% 10% 7% ? constipation 3% 3% 5% 6% 6% 10% dry mouth 6% 7% 7% 6% 8% ? flatulence 1% 1% 3% 2% 1% ? dizziness 6% 6% 6% 8% 9% ? abnormal dreams 1% <1% <1% 2% 3% ? itching 1% 1% 2% 3% 3% ? notes: vortioxetine and duloxetine (an snri) were directly compared in randomized clinical trials. other reported side effects of vortioxetine in clinical trials included headache, nasal symptoms, somnolence, and excessive sweating. the most common side effects reported with vortioxetine are nausea, vomiting, constipation, and sexual dysfunction, among others. with the exceptions of nausea and sexual dysfunction, these side effects were reported by less than or equal to 10% of study participants given vortioxetine. significant percentages of placebo-treated participants also report these side effects. discontinuation of treatment due to adverse effects in clinical trials was 8% with vortioxetine versus 3% with placebo. sexual dysfunction, such as decreased libido, abnormal orgasm, delayed ejaculation, and erectile dysfunction, are well-known side effects of ssris and serotonin–norepinephrine reuptake inhibitors (snris). in clinical trials, sexual dysfunction occurred more often with vortioxetine than with placebo and appeared to be dose-dependent. the specific incidences of treatment-emergent sexual dysfunction as measured with the arizona sexual experience scale (asex) were 14 to 20% for placebo and 16 to 34% for vortioxetine over a dosage range of 5 to 20 mg/day. the incidence of sexual dysfunction with vortioxetine was similar to that with the snri duloxetine, which had an incidence of 26 to 28% at the used dosage of 60 mg/day. however, treatment-emergent sexual dysfunction caused by a prior ssri was better improved by switching to vortioxetine than by switching to the ssri escitalopram. in another study, vortioxetine at a dosage of 10 mg/day though not at 20 mg/day produced less sexual dysfunction than the ssri paroxetine. these findings suggest that although vortioxetine can still cause sexual dysfunction itself, it may cause somewhat less sexual dysfunction than ssris and might be a useful alternative option for people experiencing sexual dysfunction with these medications. the rates of voluntarily or spontaneously reported sexual dysfunction with vortioxetine are much lower than with the asex, ranging from <1 to 5% for vortioxetine versus <1 to 2% for placebo in clinical trials. sexual dysfunction with vortioxetine at different doses in clinical trials quantification method group placebo vortioxetine duloxetine 5 mg/day 10 mg/day 15 mg/day 20 mg/day 60 mg/day measured by asex men 14% 16% 20% 19% 29% 26% women 20% 22% 23% 33% 34% 28% spontaneously reported men 2% 3% 4% 4% 5% ? women <1% <1% 1% <1% 2% ? notes: vortioxetine and duloxetine (an snri) were directly compared in randomized clinical trials. significant changes in body weight (gain or loss) were not observed with vortioxetine in clinical trials. vortioxetine might cause less emotional blunting than ssris and snris based on a couple of preliminary clinical studies. if vortioxetine is used in combination with other serotonergic drugs like maois or ssris, this may result in serotonin syndrome. interactions vortioxetine is metabolized primarily by the cytochrome p450 enzyme cyp2d6. inhibitors and inducers of cyp2d6 may modify the pharmacokinetics of vortioxetine and necessitate dosage adjustments. bupropion, a strong cyp2d6 inhibitor, has been found to increase peak levels of vortioxetine by 2.1-fold and total vortioxetine levels by 2.3-fold (bupropion dosed at 300 mg/day and vortioxetine dosed at 10 mg/day). the incidence of side effects with vortioxetine, like nausea, headache, vomiting, and insomnia, was correspondingly increased with the combination. other strong cyp2d6 inhibitors, like fluoxetine, paroxetine, and quinidine, may have similar influences on the pharmacokinetics of vortioxetine, and it is recommended that the dosage of vortioxetine be reduced by half when it is administered in combination with such medications. lesser interactions have additionally been identified for vortioxetine with the cytochrome p450 inhibitors ketoconazole and fluconazole. rifampicin, a strong and broad cytochrome p450 inducer (though notably not of cyp2d6), has been found to decrease peak levels of vortioxetine by 51% and total levels of vortioxetine by 72% (rifampicin dosed at 600 mg/day and vortioxetine at 20 mg/day). similar influences on vortioxetine pharmacokinetics may also occur with other strong cytochrome p450 inducers like carbamazepine and phenytoin. as such, it is recommended that increasing vortioxetine dosage be considered when it is given in combination with strong cytochrome p450 inducers. the maximum recommended dose should not exceed three times the original vortioxetine dose. vortioxetine and its metabolites show no meaningful interactions with a variety of assessed cytochrome p450 enzymes and transporters (e.g., p-glycoprotein) and hence vortioxetine is not expected to importantly influence the pharmacokinetics of other medications. the combination of vortioxetine with maois, including other maois like linezolid and intravenous methylene blue, may cause serotonin syndrome and is contraindicated. the risk of serotonin syndrome may also be increased when vortioxetine is combined with other serotonergic drugs, like ssris, snris, tricyclic antidepressants (tcas), triptans, tramadol, tryptophan, buspirone, st john's wort, fentanyl, and lithium, among others. however, vortioxetine is not considered to be contraindicated with serotonergic medications besides maois. pharmacology pharmacodynamics activities of vortioxetine at human molecular targets target affinity functional activity action ki (nm) ic50 / ec50 (nm) ia (%) sert 1.6 5.4 – inhibition net 113 – – inhibition 5-ht1a 15 200 96 agonist 5-ht1b 33 120 55 partial agonist 5-ht1d 54 370 – antagonist 5-ht2c 180 – – – 5-ht3a 3.7 12 – antagonist 5-ht7 19 450 – antagonist β1-adr. 46 – – – note: no significant activities at 70 other molecular targets (>1,000 nm) (including e.g. the dat). sources: vortioxetine increases serotonin concentrations in the brain by inhibiting its reuptake in the synapse, and also modulates (activates or blocks) certain serotonin receptors. this puts it in the class of serotonin modulators and stimulators, which also includes vilazodone. more specifically, vortioxetine is a serotonin reuptake inhibitor, agonist of the serotonin 5-ht1a receptor, partial agonist of the 5-ht1b receptor, and antagonist of the serotonin 5-ht1d, 5-ht3, and 5-ht7 receptors, as well as an apparent ligand of the β1-adrenergic receptor. in terms of functional activity however, vortioxetine appears to be much more potent on serotonin reuptake inhibition and 5-ht3 receptor antagonism than for its interactions with the other serotonin receptors. whereas vortioxetine has ic50 or ec50 values of 5.4 nm for the sert and 12 nm for the 5-ht3 receptor, its values are 120 to 450 nm for the 5-ht1a, 5-ht1b, 5-ht1d, and 5-ht7 receptors. this translates to about 22- to 83-fold selectivity for sert inhibition and 10- to 38-fold selectivity for 5-ht3 antagonism over activities at the other serotonin receptors. it has been claimed that the serotonin transporter (sert) and 5-ht3 receptor may be primarily occupied at lower clinical doses of vortioxetine and that the 5-ht1b, 5-ht1a, and 5-ht7 receptors may additionally be occupied at higher doses. occupancy of the serotonin transporter with vortioxetine in young men was found to be highest in the raphe nucleus with median occupancies of 25%, 53%, and 98% after 9 days of administration with 2.5, 10, and 60 mg/day vortioxetine. in another study, serotonin transporter occupancy in men was 50%, 65%, and ≥80% for 5, 10, and 20 mg/day vortioxetine. based on its clinical efficacy (e.g., at 5 mg/day), it appears that vortioxetine may produce antidepressant effects at sert occupancy as low as 50%. this is in apparent contrast to ssris and snris, which appear to require a minimum of 70 to 80% occupancy for antidepressant efficacy. these findings are suggestive that the antidepressant effects of vortioxetine may be mediated by serotonin receptor interactions in addition to serotonin reuptake inhibition. a study found no significant occupancy of the 5-ht1a receptor with vortioxetine at 30 mg/day for 9 days, which suggests that at least this specific serotonin receptor may not be involved in the clinical pharmacology of vortioxetine. however, methodological concerns were noted that may limit the interpretability of this result. occupancy of other serotonin receptors like 5-ht3 and 5-ht7 by vortioxetine in humans does not seem to have been studied. in relation to the preceding, the contribution of serotonin receptor interactions to the antidepressant effects of vortioxetine is unknown and remains to be established. uncertainties remain about whether vortioxetine is indeed a clinically multimodal antidepressant or whether it is effectively " another selective serotonin reuptake inhibitor". antagonism of the 5-ht3 receptor has been found to enhance the increase in brain serotonin levels produced by serotonin reuptake inhibition in animal studies. whether or not the 5-ht3 receptor antagonism of vortioxetine likewise does this in humans or contributes