Vortioxetine

Vortioxetine

Systematic (IUPAC) name
1-[2-(2,4-Dimethyl-phenylsulfanyl)-phenyl]piperazine
Clinical data
Trade names	Trintellix, Brintellix
License data	EU EMA: Brintellix US FDA: Vortioxetine
Pregnancy category	US: C (Risk not ruled out)
Routes of administration	Oral
Legal status
Legal status	℞ (Prescription only)
Pharmacokinetic data
Bioavailability	75% (peak at 7–11 hours)
Protein binding	98%
Metabolism	extensive hepatic, primarily CYP2D6-mediated oxidation
Biological half-life	66 hours
Excretion	59% in urine, 26% in feces
Identifiers
CAS Number	508233-74-7
ATC code	N06AX26 (WHO)
PubChem	CID 9966051
IUPHAR/BPS	7351
ChemSpider	8141643
KEGG	D10184
ChEBI	CHEBI:76016
Synonyms	Lu AA21004
Chemical data
Formula	C18H22N2S
Molar mass	298.45 g/mol (379.36 as hydrobromide)
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 Key:YQNWZWMKLDQSAC-UHFFFAOYSA-N
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Vortioxetine (vor-tye-OKS-e-teen, trade name Trintellix) is an atypical antidepressant (a serotonin modulator and stimulator) made by Lundbeck and Takeda.^[1]

Medical use

Vortioxetine is used as first-line treatment for major depressive disorder.^{[1][2][3][4][5]}

Side effects

The most common side effects reported with vortioxetine are nausea, diarrhea, dry mouth, constipation, vomiting, flatulence, dizziness, and sexual dysfunction.^[1] Vortioxetine used alone in high dose or in combination with other medications, such as other antidepressants, can produce a potentially life-threatening drug reaction known as serotonin syndrome.^[1]

Incidence of sexual dysfunction is reportedly higher in patients taking vortioxetine than in people taking placebos but appears to be lower than in people taking other antidepressants^[1][5]

Pharmacodynamics

Vortioxetine is a so-called "serotonin modulator and stimulator".<ref name="urlLundbeck's "Serotonin Modulator and Stimulator" Lu AA21004: How Novel? How Good? - GLG News">"Lundbeck's "Serotonin Modulator and Stimulator" Lu AA21004: How Novel? How Good? - GLG News".</ref> It has been shown to possess the following pharmacological actions:^[1][6][7]

• Serotonin transporter (SERT) blocker (i.e. serotonin reuptake inhibitor (SRI)) — K_i (binding affinity) = 1.6 nM, IC₅₀ = 5.4 nM
• Norepinephrine transporter (NET) blocker — K_i = 113 nM
• 5-HT_1A receptor high-efficacy partial agonist/near-full agonist — K_i = 15 nM, IA = 80%
• 5-HT_1B receptor partial agonist — K_i = 33 nM
• 5-HT_1D receptor antagonist — K_i = 54 nM
• 5-HT_3A receptor antagonist — K_i = 3.7 nM
• 5-HT₇ receptor antagonist — K_i = 19 nM
• β₁-Adrenergic receptor ligand — K_i = 46 nM^[6]

Pharmacokinetics

Vortioxetine reaches peak plasma concentration (C_max) within 7 to 11 hours post-administration (T_max), and its mean terminal half-life (t½) is ≈ 66 hours. Steady-state plasma concentrations are typically reached within two weeks.^[1] It has no active metabolites (i.e. it is not a prodrug).^[1]

Research

Vortioxetine has been studied in several clinical trials as a potential treatment for general anxiety disorder but results were inconsistent.^[8][9]

History

Vortioxetine was discovered by scientists at Lundbeck who reported the rationale and synthesis for the drug (then called Lu AA21004) in a 2011 paper.^[6][10]

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.^[11]

Vortioxetine was approved by the U.S. FDA for the treatment of major depressive disorder (MDD) in adults in September, 2013,^[12] and it was approved in Europe later that year.^[13]

Vortioxetine was previously trademarked as 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 ticagrelor (Brilinta).^[14]

See also

• Tedatioxetine
• Paroxetine
• Buspar
• Vilazodone — a recently FDA-approved antidepressant with a similar dual mechanism of action.

References

1. US Label Last updated July 2014 after review in September, 2014. Versions of label are available at FDA index page Page accessed January 19, 2016
2. [No authors listed] Vortioxetine. Aust Prescr. 2015 Jun;38(3):101-2. PMID 26648632 Free full text
3. "Relative efficacy and tolerability of vortioxetine versus selected antidepressants by indirect comparisons of similar clinical studies.". Curr Med Res Opin 30: 2589–606. Oct 10, 2014. doi:10.1185/03007995.2014.969566. PMID 25249164.
4. Köhler S, Cierpinsky K, Kronenberg G, Adli M. The serotonergic system in the neurobiology of depression: Relevance for novel antidepressants. J Psychopharmacol. 2016 Jan;30(1):13-22. PMID 26464458
5. Kelliny M, Croarkin PE, Moore KM, Bobo WV. Profile of vortioxetine in the treatment of major depressive disorder: an overview of the primary and secondary literature. Ther Clin Risk Manag. 2015 Aug 12;11:1193-212. PMID 26316764 Free full text
6. 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.
7. 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.
8. Pae CU et al. Vortioxetine, a multimodal antidepressant for generalized anxiety disorder: a systematic review and meta-analysis. J Psychiatr Res. 2015 May;64:88-98. PMID 25851751
9. Reinhold JA, Rickels K. Pharmacological treatment for generalized anxiety disorder in adults: an update. Expert Opin Pharmacother. 2015;16(11):1669-81. PMID 26159446
10. Sanchez C, Asin KE, Artigas F Vortioxetine, a novel antidepressant with multimodal activity: review of preclinical and clinical data. Pharmacol Ther. 2015 Jan;145:43-57. PMID 25016186 Free full text
11. Daniel Beaulieu for First Word Pharma. September 5th, 2007 Lundbeck, Takeda enter strategic alliance for mood disorder, anxiety drugs
12. FDA approves new drug to treat major depressive disorder, U.S. Food and Drug Administration Press Announcement.
13. EMA Brintellix page at EMA site Page accessed January 19, 2016
14. 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. Retrieved 2016-05-02.