Wednesday, January 20, 2016

Vortioxetine | Antidepressant | Treatment for Major Depressive Disorder | Treatment for Generalized Anxiety Disorder | SERT Inhibitior | 5-HT Receptor Modulator

Vortioxetine [1-[2-(2,4-Dimethylphenyl-sulfanyl)-phenyl]-piperazine] is an orally administered small molecule developed as once-daily treatment of major depressive disorder (MDD) and generalized anxiety disorder (GAD). As a drug, Vortioxetine is a bis-aryl-sulphanyl amine compound that combines serotonin (5-HT) reuptake inhibition with other characteristics, including receptor activity modulation.

Vortioxetine: 2D and 3D Structure

Vortioxetine binds to the human serotonin (5-HT) transporter (SERT) with high affinity (Ki = 1.6 nM) and is a potent inhibitor of serotonin reuptake (IC50 = 5.4 nM), whereas its affinity for transporters of noradrenaline (Ki = 113 nM) and dopamine (Ki greater than 1000 nM) is much lower or negligible. The drug also has a broad receptor-binding profile, binding to the 5-HT1A receptor (Ki = 15 nM) where it acts as an agonist, the 5-HT1B receptor (Ki = 33 nM) where it acts as a partial agonist, and the 5-HT1D, 5-HT3 and 5-HT7 receptors (Ki = 54, 3.7 and 19 nM, respectively) where it displays antagonistic properties [1, 2].

Animal and in vitro studies indicate that several neurotransmitter systems may be impacted by vortioxetine, with the drug enhancing levels of 5-HT, noradrenaline, dopamine, acetylcholine and histamine in certain areas of the brain, as well as modulating γ-aminobutyric acid and glutamate neurotransmission. Results from additional animal models suggest vortioxetine may also improve measures of cognitive function, such as memory. In healthy volunteers, single or repeated administration of vortioxetine (10 mg) did not impair cognitive function, psychomotor performance or driving ability in a placebo-controlled study.

In September 2013, Vortioxetine was approved as Brintellix for the once-daily treatment of adults with MDD in the USA and one month later, EMA approved it as it first in line treatment for Europeans with MDD. It is marketed as Trintellix in Canada.

Vortioxetine was discovered by scientists at Lundbeck, where it was known as Lu AA21004. Takeda and Lundbeck entered into a strategic alliance to co-develop and co-commercialise vortioxetine and tedatioxetine in Japan and the USA in September 2007. The two companies will jointly complete product development, which will be funded primarily by Takeda, and the companies will share revenue generated in the USA and Japan.

Vortioxetine is administered orally at a starting dosage of 10 mg/day, with the dosage increased to 20 mg/day, as tolerated; 5 mg/ day may be considered if higher dosages are not tolerated. Dosages greater than 20 mg/day have not been assessed for efficacy or safety in controlled trials.

Vortioxetine Synthesis

WO2007144005A1: Industrial process 

J Med Chem 201154(9), 3206-3221: (also see Ref. 3; it has same details)



Tolerability data from three 52-week, open-label, extension studies (NCT00694304, NCT00707980 and NCT01323478) comprising of patients taking vortioxetine (2.5-20 mg/day) confirm that greater than 70% of patients experienced adverse events (AEs). The most frequent (greater than 10% occurrence) being nausea, headache, nasopharyngitis and dizziness; where reported, sexual dysfunction adverse events were uncommon. 

Serious adverse events occurred in some patients, with those considered to be vortioxetine related including left hemispheric ischaemic stroke, tachycardia (paroxysmal and supraventricular), depression and major depression.

Moreover, some patients who abruptly discontinue vortioxetine 15 or 20 mg/day may experience symptoms such as mood swings, sudden outburst of anger, headache, dizziness, muscle tension or runny nose within the first week post discontinuation.

1. Gibb, A.; et. al. Vortioxetine: first global approval. Drugs 2014, 74(1), 135-145.
2. Bang-Andersen, B.; et. al. Discovery of 1-[2-(2,4-dimethylphenylsulfanyl)phenyl]piperazine (Lu AA21004): a novel multimodal compound for the treatment of major depressive disorder. J Med Chem 2011, 54(9), 3206-3221.
3. Bang-Andersen, B.; et. al. 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl] piperazine as a compound with combined serotonin reuptake, 5-ht3 and 5-ht1a activity for the treatment of cognitive impairment WO2007144005A1