Vortioxetine

Vortioxetine

Systematic (IUPAC) name
1-[2-(2,4-Dimethyl-phenylsulfanyl)-phenyl]piperazine
Clinical data
Trade names	Brintellix
Licence data	EMA:Link, US FDA:link
Pregnancy category	US: C (Risk not ruled out)
Legal status	℞ (Prescription only)
Routes of administration	Oral
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 Y
ATC code	N06AX26 (WHO)
PubChem	CID: 9966051
IUPHAR/BPS	7351
ChemSpider	8141643 N
KEGG	D10184 N
ChEBI	CHEBI:76016 N
Synonyms	Lu AA21004
Chemical data
Formula	C18H22N2S
Molecular 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 N Key:YQNWZWMKLDQSAC-UHFFFAOYSA-N N
NY (what is this?)  (verify)

Vortioxetine (vor-tye-OKS-e-teen, trade name Brintellix (BRIN-tel-ix) and Trintellix in Canada) is an atypical antidepressant (a serotonin modulator and stimulator) made by Lundbeck and Takeda. On September 30, 2013, it was approved by the U.S. FDA for the treatment of major depressive disorder (MDD) in adults. Vortioxetine was also investigated as a treatment for generalized anxiety disorder (GAD) but was not found to be superior to placebo.

Following a positive opinion by the Committee for Medicinal Products for Human Use (CHMP) in October 2013, Lundbeck announced December 27, 2013, that European marketing authorization for Brintellix had been obtained.

Depression

In May 22, 2011, Lundbeck presented the results of four phase III trials on vortioxetine at the 2011 Annual Meeting of the American Psychiatric Association. A statistically significant effect was shown in two of the studies (one for active treatment using the Hamilton Depression Rating Scale (HAM-D), the second as a maintenance treatment), vortioxetine failed to prove superiority over placebo in a third (again using the HAM-D) and the fourth was nullified by an exceptionally high placebo response (according to the Montgomery-Åsberg Depression Rating Scale (MADRS)).

In July 2011, Lundbeck published the results of a double-blind, randomized, placebo-controlled clinical trial with venlafaxine as an active reference. It was found to be superior to placebo in treating MDD. Similarly, in May 2012, Lundbeck published the results of a double-blind, randomized, placebo-controlled clinical trial with duloxetine evaluating vortioxetine in elderly depressed patients, and it was found superior to placebo.

In May 2012, Lundbeck disclosed the results of three phase III clinical trials, showing vortioxetine's superiority over placebo according to the MADRS.

In August 2012, a randomized, double-blind trial confirms the superiority of vortioxetine over placebo according to all measures, except the Sheehan Disability scale.

In September 2012, a randomised, double-blind trial reveals that a dose of 5 mg shows superiority over placebo only in patients that suffer from comorbid anxiety. This is consistent with results from another trial published in December 2012, demonstrating that 2.5 mg and 5 mg doses are ineffective.

Some 2014 studies showed Vortioxetine was effective and well tolerated after inadequate response to SSRI/SNRI, as initial agent up to 20 mg, and as maintenance use lasting 52 weeks.

A 2014 Meta-analysis of 7 randomized trials concluded Vortioxetine had significant reductions vs placebo in depression scores and patients with 50% reduction. Vortioxetine was ranked among 7 antidepressants with different mechanisms, placing vortioxetine greater efficacy than escitalopram, vilazodone, and sertraline with better tolerability, concluding that Vortioxetine has a favorable combination of comparable effect and excellent tolerability.

Anxiety

In August 2012, contradictory results of two randomized, double-blind trial were published. The first demonstrated vortioxetine's superiority over the placebo, but the second showed no efficacy, leading the authors to question the designs of the different trials. Two studies on adult GAD disorders which concluded in 2014 found no effect at 8 weeks with up to 10 mg.

Other effects

Vortioxetine enhances some forms of memory in rats. This finding has not been demonstrated in human trials.

Vortioxetine significantly improved objective and subjective measures of cognitive function in adults with recurrent Major Depression Disorder.

Side effects

The most common side effects reported with vortioxetine are nausea, diarrhea, dry mouth, constipation, vomiting, flatulence, dizziness, and sexual dysfunction. 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.

Incidence of sexual dysfunction is reportedly higher in patients taking vortioxetine than in patients taking placebos, but lower than in patients taking venlafaxine.

Pharmacodynamics

Vortioxetine is a so-called "serotonin modulator and stimulator". It has been shown to possess the following pharmacological actions:

• 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

It has also been shown that vortioxetine increases extracellular levels of acetylcholine and histamine in the rat medial prefrontal cortex following contextual fear conditioning and may be useful in the treatment of Alzheimer's disease.

Pharmacokinetics

Vortioxetine is indicated for the treatment of major depressive disorder (MDD) in the United States and is supplied in 5 mg, 10 mg, 15 mg and 20 mg tablets. The drug 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. No differences were observed between the fed and fasting states, and therefore it may be taken with or without food at the patient's discretion. It has no active metabolites (i.e. it is not a prodrug).

Patients typically initiate drug therapy at 10 mg daily, which may be subsequently increased to 20 mg daily. In the case that the initial 10 mg dosing is poorly tolerated, the doctor/patient may elect to decrease the maintenance dose to 5 mg per day, though available evidence demonstrating clinical efficacy at this lower dosage is not entirely conclusive and is questionably reliable. Likewise, though the prescribing information invariably recommends that the maintenance dose be increased to 20 mg/day, there is equally unsatisfying data to prove that there is any clinically significant difference in regards to success and remission rates at higher doses.

While linear kinetics follow as expected, actual efficacy figures provided show only fractional improvements in those patients in the group receiving a higher dose of 20 mg/day (based on deviation from baseline, which compare 10 mg/day vs. 20 mg/day groups). It would not be true to state that the reported efficacy data (across documented trials) highlights any linear (positive) correlations to patient doses. While there is a positive correlation, the amount of variance in efficacy between tiers is clinically unremarkable. Further studies are likely needed to elucidate such inconsistencies that destabilize confidence in the currently published clinical trial outcomes.

See also

• Tedatioxetine
• Paroxetine
• Buspar
• Vilazodone — a recently FDA-approved antidepressant with a similar dual mechanism of action.
• Serotonin modulator and stimulator — also, commonly "SMS" or simply "serotonin modulator".