FDA Panel Backs Vortioxetine for Cognitive Dysfunction in MDD

Pauline Anderson

February 08, 2016

The US Food and Drug Administration's (FDA's) Psychopharmacologic Drug Advisory Committee has determined that there is substantial evidence to support claims that vortioxetine (Brintellix) is effective in the treatment of cognitive dysfunction in patients with major depressive disorder (MDD).

The FDA panel voted 8 to 2 that substantial evidence was presented to support the claim, the drug's manufacturers, Takeda Pharmaceutical Company Limited and H. Lundbeck A/S, announced in a press release.

"This positive vote underscores the value of the robust research we've conducted on cognitive symptoms, which we've pursued knowing that patients need options," said Anders Gersel Pedersen, MD, PhD, executive vice president and head of drug development at Lundbeck, in the release.

During the advisory committee meeting, panel members discussed whether cognitive dysfunction in patients with MDD represents an appropriate target for drug development and also whether there is substantial evidence supporting a claim that vortioxetine is effective in treating certain aspects of cognitive dysfunction in patients with MDD.

Common cognitive symptoms in patients with MDD include difficulty concentrating, indecisiveness, and trouble thinking.

The advisory committee's input will be considered by the FDA in its review of the vortioxetine supplemental new drug application (sNDA), which was accepted for review in August 2015.

The FDA approved vortioxetine in 2013 for the treatment of MDD in adults. The agency is expected to make a decision on this new sNDA by March 28, according to the press release.

"We are pleased that this sNDA represents the first regulatory submission to the FDA on this topic, and we look forward to working with the agency as they complete their review," said Dr Pedersen.

The prevalence of cognitive dysfunction associated with depression is high, according to background information in the press release. In a 3-year prospective study of people treated for depression, cognitive symptoms (defined as diminished ability to think or concentrate and/or indecisiveness) was reported 94% of the time during acute major depressive episodes and 44% of the time during remission.

The advisory committee reviewed data from two studies (FOCUS and CONNECT), both 8-week, randomized, double-blind, placebo-controlled studies of vortioxetine 10 and 20 mg/day in adults with MDD. The studies used a neuropsychological test of cognitive performance (the Digit Symbol Substitution Test).

The mechanism of the antidepressant action of vortioxetine is not fully understood. It is an inhibitor of serotonin (5-HT) reuptake but also an agonist at 5-HT1A receptors, a partial agonist at 5-HT1B receptors, and an antagonist at 5-HT3, 5-HT1D, and 5-HT7 receptors.

The contribution of each of these activities to the antidepressant effect has not been established. Vortioxetine is considered to be the first and only compound with this combination of pharmacodynamic activity.

The World Health Organization has issued an anatomic therapeutic chemical (ATC) code for vortioxetine that places it in the category of "other" antidepressants.

The most commonly observed adverse events in patients with MDD who were treated with MDD in controlled studies were nausea, constipation, and vomiting. Overall, the company reported 5% to 8% of the patients who received vortioxetine 5 to 20 mg/day in short-term trials discontinued treatment because of an adverse reaction, the most common being nausea, compared with 4% of placebo-treated patients.

In clinical studies, vortioxetine had no significant effect on body weight, as measured by the mean change from baseline in 6- to 8-week controlled studies.

The recommended starting dose of vortioxetine is 10 mg once daily. The dose should then be increased to 20 mg/day, as tolerated, because research has shown that higher doses yield better treatment effects.

Sources: Press release from Takeda and Lundbeck; FDA meeting briefing materials.


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