Vortioxetine

Vortioxetine, sold under the brand names Trintellix and Brintellix among others, is a medication used to treat major depressive disorder.[3] Effectiveness is viewed as similar to that of other antidepressants.[3] In the United Kingdom, it is only recommended in people who have not improved sufficiently on two other antidepressants.[4] It is taken by mouth.[3]

Vortioxetine
Clinical data
Pronunciation/vɔːrtiˈɒksətiːn/ vor-tee-OK-sə-teen
Trade namesTrintellix, Brintellix, others
Other namesLu AA21004
AHFS/Drugs.comMonograph
MedlinePlusa614003
License data
Pregnancy
category
Routes of
administration		By mouth (film-coated tablets)
ATC code
Legal status
Legal status
  • AU: S4 (Prescription only)
  • US: ℞-only
  • EU: Rx-only [2]
  • In general: ℞ (Prescription only)
Pharmacokinetic data
Bioavailability75% (peak at 7–11 hours)
Protein binding98%
MetabolismExtensive Liver, primarily CYP2D6-mediated oxidation
Elimination half-life66 hours
Excretion59% in urine, 26% in feces
Identifiers
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
CompTox Dashboard (EPA)
ECHA InfoCard100.258.748
Chemical and physical data
FormulaC18H22N2S
Molar mass298.45 g·mol−1
3D model (JSmol)
 NY (what is this?)  (verify)

Common side effects include constipation and nausea.[3] Serious side effects may include suicide in those under the age of 25, serotonin syndrome, bleeding, mania, and SIADH.[3] A withdrawal syndrome may occur if the dose is rapidly decreased.[3] Use during pregnancy and breastfeeding is not generally recommended.[4] It is classified as a serotonin modulator.[3] How it works is not entirely clear but is believed to be related to increasing serotonin levels.[3]

It was approved for medical use in the United States in 2013.[3] In 2017, it was the 312th most commonly prescribed medication in the United States, with more than one million prescriptions.[5]

Medical uses

Vortioxetine is used as a treatment for major depressive disorder.[3] Effectiveness appear to be similar to other antidepressants.[3] It may be used when other treatments have failed.[6][7][8][9] 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 SSRIs which are typical first line treatments.[10]

Vortioxetine is also used off-label for anxiety.[11] 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).[12] A 2019 meta-analysis found that vortioxetine didn't produce statistically significant results over the placebo in the symptoms, quality of life and remission rates of the generalised anxiety disorder, but it was well tolerated.[13]

Adverse effects

The most common side effects reported with vortioxetine are nausea, diarrhea, dry mouth, constipation, vomiting, flatulence, dizziness, and sexual dysfunction.[6] However, with the singular exception of nausea, these side effects occurred in less than 10% of study participants given the active drug, with up to 8% of placebo-treated participants reporting the same side effects.

If vortioxetine is prescribed alongside traditional selective serotonin reuptake inhibitors (SSRIs), or other serotonergic drugs, this can induce the potentially life-threatening serotonin syndrome.[6]

Incidence of sexual dysfunction is only slightly higher in patients taking vortioxetine than in people taking placebos and occurs in less than 10% of vortioxetine-treated patients. As such, vortioxetine may be appropriate for people who have suffered sexual side effects from other antidepressant medications.[6][9]

Pharmacology

Pharmacodynamics

Vortioxetine increases serotonin concentrations in the brain by inhibiting its reuptake in the synapse, and by modulating (activating certain receptors while blocking, or antagonizing, others) certain serotonin receptors. This puts it in the class of serotonin modulators and stimulators which also includes vilazodone.[14] It has been shown to possess the following pharmacological actions:[6][15][16][17][18][19]

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-HT3* 3.7 12 — Antagonist
5-HT7* 19 450 — Antagonist
β1 46[15] — — —

* Human isoforms

Pharmacokinetics

Vortioxetine reaches peak plasma concentration (Cmax) within 7 to 11 hours post-administration (Tmax), and its mean terminal half-life (T½) is ≈ 66 hours.

Steady-state mean Cmax values were 9, 18, and 33 ng/mL following doses of 5, 10, and 20 mg/day. Steady-state plasma concentrations are typically reached within two weeks.[6]

Vortioxetine's pKa values are determined to be 9.1 (± 0.1) and 3.0 (± 0.2) according to Australian Public Assessment Report for vortioxetine hydrobromide.[20]

History
10 mg tablets of vortioxetine (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.[15][21]

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 upfront, 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.[22]

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,[23] and it was approved in Europe later that year.[24]

Society and culture

It is made by the pharmaceutical companies Lundbeck and Takeda.[6]

Names

Vortioxetine was previously sold under the brand name Brintellix in the United States, but on May 2, 2016, the US FDA approved a name change to Trintellix in order to avoid confusion with the blood-thinning medication Brilinta (ticagrelor).[25]

See also
  • Ampreloxetine

References
  1. "Brintellix (vortioxetine (as hydrobromide)) Product Information" (PDF). Therapeutic Goods Administration.
  2. "Brintellix EPAR". European Medicines Agency (EMA). Retrieved 15 January 2021.
  3. "Vortioxetine Hydrobromide Monograph for Professionals". Drugs.com. American Society of Health-System Pharmacists. Retrieved 18 March 2019.
  4. British national formulary : BNF 76 (76 ed.). Pharmaceutical Press. 2018. p. 376. ISBN 9780857113382.
  5. "Vortioxetine Hydrobromide - Drug Usage Statistics". ClinCalc. Retrieved 11 April 2020.
  6. "Trintellix- vortioxetine tablet, film coated". DailyMed. 26 July 2019. Retrieved 16 November 2020.
  7. Connolly, KR; Thase, ME (2016). "Vortioxetine: a New Treatment for Major Depressive Disorder". Expert Opinion on Pharmacotherapy. 17 (3): 421–31. doi:10.1517/14656566.2016.1133588. PMID 26679430. S2CID 40432194. The authors suggest that vortioxetine is currently a good second-line antidepressant option and shows promise, pending additional long-term data, to become a first-line antidepressant option.
  8. Köhler, Stephan; Cierpinsky, Katharina; Kronenberg, Golo; Adli, Mazda (2016). "The serotonergic system in the neurobiology of depression: Relevance for novel antidepressants". Journal of Psychopharmacology. 30 (1): 13–22. doi:10.1177/0269881115609072. PMID 26464458. S2CID 21501578.
  9. Bobo, William; Kelliny, Marc; Croarkin, Paul; Moore, Katherine (2015). "Profile of vortioxetine in the treatment of major depressive disorder: An overview of the primary and secondary literature". Therapeutics and Clinical Risk Management. 11: 1193–212. doi:10.2147/TCRM.S55313. PMC 4542474. PMID 26316764.
  10. Koesters, Markus; Ostuzzi, Giovanni; Guaiana, Giuseppe; Breilmann, Johanna; Barbui, Corrado (2017-07-05). "Vortioxetine for depression in adults". The Cochrane Database of Systematic Reviews. 7: CD011520. doi:10.1002/14651858.CD011520.pub2. ISSN 1469-493X. PMC 6483322. PMID 28677828.
  11. Pae, Chi-Un; Wang, Sheng-Min; Han, Changsu; Lee, Soo-Jung; Patkar, Ashwin A.; Masand, Praksh S.; Serretti, Alessandro (May 2015). "Vortioxetine, a multimodal antidepressant for generalized anxiety disorder: a systematic review and meta-analysis". Journal of Psychiatric Research. 64: 88–98. doi:10.1016/j.jpsychires.2015.02.017. ISSN 1879-1379. PMID 25851751.
  12. Fu, Jie; Peng, Lilei; Li, Xiaogang (2016-04-19). "The efficacy and safety of multiple doses of vortioxetine for generalized anxiety disorder: a meta-analysis". Neuropsychiatric Disease and Treatment. 12: 951–959. doi:10.2147/NDT.S104050. ISSN 1176-6328. PMC 4844447. PMID 27143896.
  13. Qin, Bin; Huang, Guangsu; Yang, Qian; Zhao, Mingjun; Chen, Hong; Gao, Wen; Yang, Mingxiu (November 2019). "Vortioxetine treatment for generalised anxiety disorder: a meta-analysis of anxiety, quality of life and safety outcomes". BMJ Open. 9 (11): e033161. doi:10.1136/bmjopen-2019-033161. PMC 6924794. PMID 31784448.
  14. "Lundbeck's "Serotonin Modulator and Stimulator" Lu AA21004: How Novel? How Good? - GLG News". Archived from the original on 2011-07-24.
  15. Bang-Andersen B, Ruhland T, Jørgensen M, et al. (May 2011). "Discovery of 1-[2-(2,4-dimethylphenylsulfanyl)phenyl]piperazine (Lu AA21004): a novel multimodal compound for the treatment of major depressive disorder". Journal of Medicinal Chemistry. 54 (9): 3206–21. doi:10.1021/jm101459g. PMID 21486038.
  16. N. Moore; B. Bang-Andersen; L. Brennum; K. Fredriksen; S. Hogg; A. Mork; T. Stensbol; H. Zhong; C. Sanchez; D. Smith (August 2008). "Lu AA21004: a novel potential treatment for mood disorders". European Neuropsychopharmacology. 18 (Supplement 4): S321. doi:10.1016/S0924-977X(08)70440-1. S2CID 54253895.
  17. Sanchez, C; Asin, KE; Artigas, F (1 January 2015). "Vortioxetine, a Novel Antidepressant with Multimodal Activity: Review of Preclinical and Clinical Data". Pharmacology & Therapeutics. 145: 43–57. doi:10.1016/j.pharmthera.2014.07.001. ISSN 1879-016X. PMID 25016186.
  18. Stahl, Stephen M. (2013-04-11). Stahl's Essential Psychopharmacology: Neuroscientific Basis and Practical Applications (4th ed.). Cambridge University Press. ISBN 978-1107686465.
  19. "BindingDB Search: BDBM50400902 1-(2-(2,4-dimethylphenylsulfanyl)phenyl)piperazine". BindingDB. Retrieved 7 December 2018.
  20. "Australian Public Assessment Report for vortioxetine hydrobromide" (PDF). p. 11. Archived (PDF) from the original on 2017-08-01. Retrieved 2018-05-05.
  21. Sanchez, C; Asin, KE; Artigas, F (2015). "Vortioxetine, a novel antidepressant with multimodal activity: review of preclinical and clinical data". Pharmacol. Ther. 145: 43–57. doi:10.1016/j.pharmthera.2014.07.001. PMID 25016186.
  22. Daniel Beaulieu for First Word Pharma. September 5th, 2007 Lundbeck, Takeda enter strategic alliance for mood disorder, anxiety drugs Archived 2016-10-10 at the Wayback Machine
  23. FDA approves new drug to treat major depressive disorder Archived 2013-10-03 at the Wayback Machine, U.S. Food and Drug Administration Press Announcement.
  24. EMA Brintellix page at EMA site Archived 2016-01-26 at the Wayback Machine Page accessed January 19, 2016
  25. Commissioner, Office of the. "Safety Alerts for Human Medical Products - Brintellix (vortioxetine): Drug Safety Communication - Brand Name Change to Trintellix, to Avoid Confusion With Antiplatelet Drug Brilinta (ticagrelor)". www.fda.gov. Archived from the original on 2016-05-05. Retrieved 2016-05-02.
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