Vortioxetine

Source: Wikipedia, the free encyclopedia.

Vortioxetine
Clinical data
Pronunciation/vɔːrtiˈɒksətiːn/ vor-tee-OK-sə-teen
Trade namesTrintellix, Brintellix, others
Other namesLu AA21004, Vortioxetine hydrobromide (JAN JP), Vortioxetine hydrobromide (USAN US)
AHFS/Drugs.comMonograph
MedlinePlusa614003
License data
Pregnancy
category
Routes of
administration		By mouth
Drug classSelective serotonin reuptake inhibitor (SSRI)[3]
ATC code
Legal status
Legal status
oxidation[12]
Elimination half-life66 hours[12]
Excretion59% in urine, 26% in feces[12]
Identifiers
  • 1-[2-(2,4-Dimethyl-phenylsulfanyl)phenyl]piperazine
JSmol)
  • CC(C=C(C)C=C1)=C1SC2=C(N3CCNCC3)C=CC=C2
  • 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 ☒N
  • Key:YQNWZWMKLDQSAC-UHFFFAOYSA-N ☒N
  (verify)

Vortioxetine, sold under the brand names Trintellix and Brintellix among others, , is an

antidepressants.[14] It is taken by mouth.[14]

Common

SIADH.[14] A withdrawal syndrome may occur if the medication is abruptly stopped or the dose is decreased.[14] Use during pregnancy and breastfeeding is not generally recommended.[15] It is classified as a serotonin modulator and stimulator.[14][16] Vortioxetine's mechanism of action is not entirely understood, but is believed to be related to increasing serotonin levels and possibly interacting with certain receptors for serotonin.[14][17][18]

It was approved for medical use in the United States in 2013.[14][19] In 2020, it was the 243rd most commonly prescribed medication in the United States, with more than 1 million prescriptions.[20][21]

Medical uses

Vortioxetine is used as a treatment for

antidepressants[14][22][23] and its effect size has been described as modest.[24] Vortioxetine may be used when other treatments have failed.[10][25][26][27] 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.[28] Vortioxetine appears to work in depressed patients with anxiety.[29]

Vortioxetine is also used

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).[35]

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.[36][37] 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.[36][37]

Contraindications

Vortioxetine is contraindicated in those taking monoamine oxidase inhibitors (MAOIs) due to the possibility of serotonin syndrome.[10]

Adverse effects

Side effects of vortioxetine at different doses in clinical trials[10][18]
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
nasal symptoms, somnolence, and excessive sweating.[38][37]

The most common side effects reported with vortioxetine are nausea, vomiting, constipation, and sexual dysfunction, among others.[10] 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.[10][38] Significant percentages of placebo-treated participants also report these side effects.[10][38] Discontinuation of treatment due to adverse effects in clinical trials was 8% with vortioxetine versus 3% with placebo.[38]

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.[18][17] 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.[18] However, treatment-emergent sexual dysfunction caused by a prior SSRI was better improved by switching to vortioxetine than by switching to the SSRI escitalopram.[10] 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.[10] 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.[10][39] 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.[17][18][10]

Sexual dysfunction with vortioxetine at different doses in clinical trials[10][18]
Quantification method Group Placebo Vortioxetine Duloxetine
5 mg/day 10 mg/day 15 mg/day 20 mg/day 60 mg/day
Measured by
ASEX
Tooltip Arizona Sexual Experience Scale 		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.[10][38]
However reports have come in from users regarding weight gain/loss since the approval of Vortioxetine.

Based on preliminary clinical studies, vortioxetine may cause less emotional blunting than SSRIs and SNRIs.[40][41]

If vortioxetine is used in combination with other serotonergic drugs like MAOIs or SSRIs, this may result in serotonin syndrome.[10]

Interactions

Vortioxetine is metabolized primarily by the cytochrome P450 enzyme CYP2D6.[12] Inhibitors and inducers of CYP2D6 may modify the pharmacokinetics of vortioxetine and necessitate dosage adjustments.[12]

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).[12] The incidence of side effects with vortioxetine, like nausea, headache, vomiting, and insomnia, was correspondingly increased with the combination.[12] 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.[12][10] Lesser interactions have additionally been identified for vortioxetine with the cytochrome P450 inhibitors ketoconazole and fluconazole.[12]

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).[12] Similar influences on vortioxetine pharmacokinetics may also occur with other strong cytochrome P450 inducers like carbamazepine and phenytoin.[12] As such, it is recommended that increasing vortioxetine dosage be considered when it is given in combination with strong cytochrome P450 inducers.[12] The maximum recommended dose should not exceed three times the original vortioxetine dose.[12][10]

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.[10][12]

The combination of vortioxetine with MAOIs, including other MAOIs like

St John's wort, fentanyl, and lithium, among others.[10] However, vortioxetine is not considered to be contraindicated with serotonergic medications besides MAOIs.[10]

Pharmacology

Pharmacodynamics

Activities of vortioxetine at human molecular targets
Target Affinity Functional activity Action
Ki (nM) IC50 / EC50 (nM) IA (%)
SERTTooltip Serotonin transporter 1.6 5.4 – Inhibition
NETTooltip Norepinephrine transporter 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 DATTooltip Dopamine transporter). Sources: [42][43]

Vortioxetine increases

β1-adrenergic receptor.[45][43][42] 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.[45] 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.[45] 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.[45] 5-HT3 antagonism appears to have a better effect on REM sleep compared to paroxetine.[46]

It has been claimed that 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.[12][47] In another study, serotonin transporter occupancy in men was 50%, 65%, and ≥80% for 5, 10, and 20 mg/day vortioxetine.[12][10]

Vortioxetine at 5 mg/day may produce antidepressant effects and result in SERT occupancy as low as 50%.[12][45][48] This is in apparent contrast to SSRIs and SNRIs, which appear to require a minimum of 70 to 80% occupancy for antidepressant efficacy.[12][45][49] These findings are suggestive that the antidepressant effects of vortioxetine may be mediated by serotonin receptor interactions in addition to serotonin reuptake inhibition.[12][45] 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.[45][13][47] However, methodological concerns were noted that may limit the interpretability of this result.[45][47][13] Occupancy of other serotonin receptors like 5-HT3 and 5-HT7 by vortioxetine in humans does not seem to have been studied.[18][45] In relation to the preceding, the contribution of serotonin receptor interactions to the antidepressant effects of vortioxetine is unknown and remains to be established.[12][10][18][17] Uncertainties remain about whether vortioxetine is indeed a clinically multimodal antidepressant or whether it is effectively "[just] another selective serotonin reuptake inhibitor".[17][18]

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.[45][13] Whether or not the 5-HT3 receptor antagonism of vortioxetine likewise does this in humans or contributes to its clinical antidepressant efficacy is unclear.[17][18] 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.[45] It was thought that the 5-HT3 receptor antagonism of vortioxetine would reduce the incidence of nausea relative to SSRIs.[45] 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.[10][18]

Pharmacokinetics

Vortioxetine levels after a single 10 mg oral dose of vortioxetine in 18 fasted and 18 fed healthy Japanese adults.[50]
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.[51]

Vortioxetine is well-

area-under-the-curve levels after a single dose versus at steady state) is 5 to 6.[12] A loading dose given intravenously has been found to achieve steady-state levels more rapidly with oral vortioxetine therapy.[51] 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.[12] Food has no influence on the pharmacokinetics of vortioxetine.[12]

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.[12][38] The plasma protein binding of vortioxetine is approximately 98 or 99%, with about 1.25 ± 0.48% free or unbound.[12][10][13]

Vortioxetine is extensively

pharmacological activity.[12]

The estimated total

elimination half-life of vortioxetine is 66 hours, with a range of 59 to 69 hours after single or multiple doses.[12] Elimination of vortioxetine is almost entirely via the liver (99%) rather than the kidneys (<1%).[12] Approximately 85% of vortioxetine was recovered in a single-dose excretion study after 15 days, with 59% in urine and 26% in feces.[12]

Pharmacogenomics

interindividual variability.[12] Dosage adjustment for CYP2D6 ultra-rapid metabolizers is considered to not be necessary.[12] Vortioxetine exposure in CYP2D6 poor metabolizers is expected to be approximately twice as high as in extensive metabolizers.[12] 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.[12] In addition to CYP2D6, CYP2C19 extensive metabolizers have 1.4-fold higher clearance of vortioxetine than poor metabolizers.[12] However, this is not considered to be clinically important and dose adjustment is not considered to be necessary based on CYP2C19 status.[12]

Chemistry

Vortioxetine (1-[2-(2,4-dimethylphenylsulfanyl)phenyl]piperazine) is a bis-aryl-sulfanyl amine as well as

derivative.[38] 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.[52]

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.[43][45]

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.[53]

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,[54] and it was approved in the European Union later that year.[55]

Society and culture

It is made by the pharmaceutical companies Lundbeck and Takeda.[10]

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).[56] Other brand names include Vantaxa, Torvox, Voxigain, Trivoxetin, Trintellix etc.

Research

Vortioxetine was under development for the treatment of

social phobia,[60] neuropathic pain,[61] and for cognitive enhancement in major depression.[62]

References

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