Vortioxetine

Vortioxetine, sold under the brand names Trintellix and Brintellix among others, is an antidepressant medication of the serotonin modulator and stimulator class used in the treatment of major depressive disorder. Its effectiveness is viewed as similar to that of other antidepressants. It is taken orally.
Common side effects include nausea, dry mouth, diarrhea, constipation, vomiting, 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. Vortioxetine's mechanism of action is not entirely understood, but is believed to be related to increasing serotonin levels and possibly interacting with certain serotonin receptors.
It was approved for medical use in the United States and in the European Union in 2013. In 2020, it was the 243rd most commonly prescribed medication in the United States, with more than 1million prescriptions.

Medical uses

Vortioxetine is used as a treatment for major depressive disorder, with its effectiveness shown to be similar to other antidepressants and its effect size has been described as modest. Vortioxetine may be used when other treatments have failed. A 2017 Cochrane review on vortioxetine determined that its place in the treatment of severe depression is unclear due to low-quality evidence and that more studies comparing vortioxetine to selective serotonin reuptake inhibitors, the typical first-line treatments, are needed. Vortioxetine appears to work in depressed patients with anxiety.
Vortioxetine is also used off label for anxiety. A 2016 review found it was not useful in generalized anxiety disorder at 2.5, 5.0, and 10 mg doses. 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 of very low-quality. In a 2020 network meta-analysis of randomized controlled trials, vortioxetine was among the lowest remission rates for generalized anxiety disorder of the included medications.
File:Effectiveness of vortioxetine at different doses versus placebo and duloxetine in the treatment of major depressive disorder in adults.png|class=skin-invert-image|thumb|left|450px|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 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, due to the possibility of serotonin syndrome.

Adverse effects

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. In clinical trials, sexual dysfunction occurred more often with vortioxetine than with placebo and appeared to be dose-dependent. Incidence of treatment-emergent sexual dysfunction as measured with the Arizona Sexual Experience Scale 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 spontaneously reported sexual dysfunction are much lower than those obtained when researchers specifically ask subjects about sexual dysfunction.
Based on preliminary clinical studies, vortioxetine may cause less emotional blunting than SSRIs and SNRIs.
Vortioxetine used in combination with other serotonergic drugs such as MAOIs or SSRIs 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. 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, has been found to decrease peak levels of vortioxetine by 51% and total levels of vortioxetine by 72%. Similar influences on vortioxetine pharmacokinetics may also occur with other strong cytochrome P450 inducers including carbamazepine and phenytoin. As such, increasing vortioxetine dosage should 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, hence vortioxetine is not expected to influence the pharmacokinetics of other medications importantly.
The combination of vortioxetine with MAOIs, including other MAOIs such as 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, 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

Vortioxetine increases serotonin concentrations in the brain by inhibiting its reuptake in the synapse, and also modulates 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-HT_1A receptor, partial agonist of the 5-HT_1B receptor, and antagonist of the serotonin 5-HT_1D, 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-HT_1A, 5-HT_1B, 5-HT_1D, 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. 5-HT₃ antagonism appears to have a better effect on REM sleep compared to paroxetine.
The serotonin transporter] and 5-HT₃ receptor are claimed to be primarily occupied at lower clinical doses of vortioxetine and that the 5-HT_1B, 5-HT_1A, 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 respectively.
Vortioxetine at 5 mg/day may produce antidepressant effects and result in 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-HT_1A 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 to its clinical antidepressant efficacy is unclear. SSRIs and 5-HT_1A 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.