The results from CONNECT, a new study that has evaluated the effect of Vortioxetine ( Brintellix ) 10-20 mg/d on aspects of cognitive function, using an objective neuropsychological test ( Digit Symbol Substitution Test or DSST ) associated with executive function, processing speed and attention, in adults with major depressive disorder ( MDD ), were presented at the 29th International College of Neuropsychopharmacology ( CINP ) World Congress in Vancouver, Canada.

In this study, adult patients with major depressive disorder, a MADRS total score greater than or equal to 26, and self-reported cognitive dysfunction were randomized to flexibly dosed Vortioxetine 10-20 mg/d ( n=198 ), placebo ( n=194 ), or the active reference ( Duloxetine 60 mg/d [ Cymbalta ]; n=210 ) included to demonstrate assay sensitivity for depression.

The primary endpoint was change from baseline to week 8 on the DSST ( ANCOVA ). Key secondary endpoints, patient-reported Perceived Deficits Questionnaire ( PDQ ) attention / concentration and planning / organization subscore 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 ( FAS ) and a mixed-effects model repeated measures ( MMRM ) approach.
Additional endpoints included MADRS total score to confirm efficacy on the overall symptoms of depression, and a prespecified path analysis to detect direct vs. indirect effects on cognition.

Vortioxetine was statistically superior to placebo on the primary endpoint of change from baseline to week 8 on the DSST ( p less than 0.05 ) and two key secondary endpoints, PDQ ( p less than 0.01 ) and CGI-I ( p less than 0.05 ).

Vortioxetine was statistically superior to placebo on the MADRS ( p less than 0.05 ) change from baseline at week eight.
In the study, a pre-specified path-analysis to detect direct vs. indirect effects of treatment on cognition indicated Vortioxetine's effect on cognitive performance was primarily a direct treatment effect rather than due to alleviation of overall depressive symptoms.
Assay sensitivity for the treatment of depression, determined by mean change from baseline to week 8 in MADRS total score versus placebo, was confirmed in this trial by the active reference Duloxetine.

In this study, common adverse events ( more than 5% ) for Vortioxetine were nausea, headache, and diarrhea.

The mechanism of the antidepressant effect of Vortioxetine is not fully understood. It 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-HT3, 5-HT1D and 5-HT7 receptors.
The contribution of each of these activities to Vortioxetine's antidepressant effect has not been established. It is considered to be the first and only compound with this combination of pharmacodynamic activity.

The most commonly observed adverse events in MDD patients treated with Vortioxetine in 6-8 week placebo-controlled studies ( incidence greater than or equal to 5% and at least twice the rate of placebo ) were nausea, constipation and vomiting.
Overall, 5 to 8% of the patients who received Vortioxetine 5 to 20 mg/day in short-term trials discontinued treatment due to an adverse reaction, the most common being nausea, compared with 4% of placebo-treated patients in these studies.

In clinical studies, Vortioxetine had no significant effect on body weight as measured by the mean change from baseline in 6-8 week placebo-controlled studies. In the 6-month, double-blind, placebo-controlled phase of a long-term study in patients who had responded to Vortioxetine during the initial 12-week, open-label phase, there was no significant effect on body weight between Vortioxetine and placebo-treated patients.
Vortioxetine has not been associated with any clinically significant effects on vital signs, including systolic and diastolic blood pressure and heart rate, as measured in placebo-controlled studies.

The recommended starting dose of Vortioxetine is 10 mg once daily without regard to meals. The dose should then be increased to 20 mg/day, as tolerated, because higher doses demonstrated better treatment effects in trials conducted in the U.S. A dose decrease down to 5 mg/day may be considered for patients who do not tolerate higher doses.
Brintellix is available as 5 mg, 10 mg and 20 mg tablets. ( Xagena )

Source: Lundbeck, 2014

XagenaMedicine2014