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Positive Results Reported for Vortioxetine (Brintellix) in Patients With Major Depressive Disorder

Treatment approved in 2013

Positive results have been reported from the CONNECT trial, which evaluated the effect of vortioxetine (Brintellix, Takeda/Lundbeck) on aspects of cognitive function — using an objective neuropsychologic evaluation (the Digit Symbol Substitution Test [DSST]) of executive function, processing speed, and attention — in adults with major depressive disorder (MDD).

The new data will be presented at the 29th International College of Neuropsychopharmacology (CINP) World Congress in Vancouver, Canada.

In the study, adult patients with MDD, a Montgomery–Åsberg Depression Scale (MADRS) total score of 26 or greater, and self-reported cognitive dysfunction were randomly assigned to receive flexibly dosed vortioxetine (10 to 20 mg/d; n = 198), placebo (n = 194), or an active reference (duloxetine 60 mg/d; n = 210) included to demonstrate assay sensitivity for depression. The trial’s primary endpoint was the change from baseline to week 8 on the DSST.

Key secondary endpoints, patient-reported Perceived Deficits Questionnaire (PDQ) attention/concentration and planning/organization subscores, and the Clinical Global Impressions–Global Improvement Scale (CGI-I) at week 8 were analyzed in a pre-specified testing sequence using the full-analysis set and a mixed-effects model of repeated measures (MMRM) approach.

Additional endpoints included the MADRS total score to confirm efficacy on the overall symptoms of depression, and a pre-specified path analysis to detect direct versus indirect effects on cognition.

Vortioxetine was statistically superior to placebo on the primary endpoint of the change from baseline to week 8 on the DSST (P < 0.05) and on two key secondary endpoints — PDQ (P < 0.01) and CGI-I (P < 0.05). Vortioxetine was also statistically superior to placebo on the MADRS (P < 0.05) change from baseline at week 8.

In the study, a pre-specified path-analysis to detect direct versus indirect effects of treatment on cognition indicated that the effect of vortioxetine on cognitive performance was primarily a direct treatment effect rather than due to the alleviation of overall depressive symptoms. Assay sensitivity for the treatment of depression — determined by the mean change from baseline to week 8 in the MADRS total score versus placebo — was confirmed in this trial by the active reference duloxetine. Common adverse events with vortioxetine included nausea, headache, and diarrhea.

Brintellix (vortioxetine) was approved by the FDA in September 2013 for the treatment of MDD in adults. The recommended starting dose is 10 mg once daily without regard to meals. The dose should then be increased to 20 mg/day, as tolerated. A dose decrease down to 5 mg/day may be considered for patients who cannot tolerate higher doses.

The mechanism of the antidepressant effect of vortioxetine is not fully understood. The drug is an inhibitor of serotonin (5-HT) reuptake, and that is thought to be a mechanism of its action. It is also an agonist at 5-HT1A receptors, a partial agonist at 5-HT1B receptors, and an antagonist at 5-HT1D, 5-HT3, and 5-HT7 receptors. The contribution of each of these activities to the antidepressant effect of vortioxetine has not been established. Vortioxetine is considered to be the first and only compound with this combination of pharmacodynamic activity. The clinical relevance of this activity is unknown.

Source: Lundbeck; June 16, 2014.

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