The European Commission granted marketing authorization for Brintellix ( Vortioxetine ) for the treatment of adults with major depressive episodes. The European approval follows approval by the FDA ( Food and Drug Administration ) in September 2013.

The approval of Brintellix was based on the review of one of the most comprehensive global clinical development programs in depression, involving more than 7,000 patients. Approximately 4,000 patients were treated with Brintellix in 12 short-term ( 6 to 8 weeks ), placebo-controlled studies of patients with an acute episode of major depression. In 9 of the 12 studies, Brintellix showed statistically significant and clinically relevant effects on depression relative to placebo.
One of these studies was a dedicated study in the elderly. The symptoms of depression were assessed using the Montgomery and Åsberg Depression Scale ( MADRS ) or Hamilton Depression Rating Scale ( HAM-D24 ). The clinical relevance was supported by significant effects observed in the proportions of responders and remitters and in the improvement in the Clinical Global Impression - Global Improvement ( CGI-I ) score. A dose response was observed with the efficacy of Brintellix increasing with higher doses.

Furthermore, efficacy of Brintellix has also been demonstrated in patients with an acute episode of major depression and with a suboptimal response to treatment with an SSRI or SNRI.
In a 12-week head-to-head study ( REVIVE ) versus the most recently approved antidepressant in the European Union ( EU ), Agomelatine ( Valdoxan, Thymanax ), Brintellix was significantly superior to Agomelatine after both 8 ( primary end point ) and 12 weeks, as measured by improvement in the MADRS total score and by the proportion of remitters and improvement in the CGI-I and Sheehan Disability Scale ( SDS ) scores.

The long-term effect of Brintellix was demonstrated in a 24-64 week, relapse-prevention study. Brintellix treatment resulted in a statistically significant longer time to relapse of depression compared to placebo. Treatment with Brintellix reduced the risk of relapse by 50% compared to placebo.

The recommended starting and treatment dose of Brintellix is 10 mg once daily in adults less than 65 years of age. The dose may be increased to a maximum of 20 mg once daily or decreased to a minimum of 5 mg once daily, depending on individual patient response.

The mechanism of action of Vortioxetine is thought to be related to its direct modulation of serotonergic receptor activity and inhibition of the serotonin ( 5-HT ) transporter. Nonclinical data indicate that Vortioxetine is a 5-HT3, 5-HT7, and 5-HT1D receptor antagonist, 5-HT1B receptor partial agonist, 5-HT1A receptor agonist and inhibitor of the 5-HT transporter, leading to modulation of neurotransmission in several systems.
In vivo non-clinical studies have demonstrated that Brintellix modulates neuronal firing and neurotransmitter release in multiple systems, resulting in enhanced levels of serotonin, noradrenaline, dopamine, acetylcholine and histamine, reduction of GABA and increase of glutamate in specific areas of the brain.
This multimodal activity is considered responsible for the antidepressant and anxiolytic-like effects and the improvement of cognitive function, learning and memory observed with Vortioxetine in animal studies.

The most common adverse reaction in patients treated with Brintellix was nausea, which was usually mild to moderate and occurred within the first two weeks of treatment. The reactions were usually transient and did not generally lead to discontinuation of therapy.

In short- and long-term clinical studies, Brintellix had no significant effect on body weight. The incidence of self-reported adverse sexual reactions was low and similar to placebo in the short- and long-term studies. In studies using the ASEX scale, no clinically relevant difference to placebo in symptoms of sexual dysfunction was seen in doses up to 10 mg/day of Brintellix. For doses above 10 mg/day an increase in TESD ( treatment-emergent sexual dysfunction ) was seen compared to placebo.
Brintellix has not been associated with any clinically significant effects on vital signs, including systolic and diastolic blood pressure and heart rate. ( Xagena )

Source: Lundbeck, 2013

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