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Vortioxetine improves cognitive performance and function in adult patients with major depression

The results from the CONNECT study showing that Vortioxetine ( Brintellix ) 10 to 20 mg/day in adults with major depressive disorder ( MDD ) met the primary study endpoint of demonstrating superiority versus placebo in cognitive function as measured by the Digit Symbol Substitution Test ( DSST ) were presented at the 29th International College of Neuropsychopharmacology ( CINP ) World Congress in Vancouver, Canada.

The objectives of this randomized, double-blind, placebo-controlled study were to evaluate the effects of Vortioxetine on cognitive function using objective neuropsychological tests associated with executive function, processing speed and attention after eight weeks of treatment in adults with major depression, while also confirming efficacy on overall symptoms of depression.

In the CONNECT study, a total of 602 subjects were randomized ( 198 on Vortioxetine, 210 on Duloxetine [ Cymbalta ], and 194 on placebo ). Adults ( 18-65 years ) with major depressive disorder, MADRS greater than or equal to 26 and self-reported cognitive dysfunction were enrolled.

The primary endpoint was change from baseline to week 8 on the Digit Symbol Substitution Test ( DSST ). Key secondary endpoints, patient-reported Perceived Deficits Questionnaire ( PDQ ) and Clinical Global Impression - Global Improvement ( CGI-I ) Scale at week 8 were analyzed in a pre-specified testing sequence using the full-analysis set ( FAS ).
Additional endpoints included the objective performance-based University of San Diego Performance-Based Skills Assessment ( UPSA ) to measure functionality, the Montgomery-Åsberg Depression Rating Scale ( MADRS ) to assess efficacy in depression, and a pre-specified path-analysis to detect direct vs indirect effects of Vortioxetine on cognitive function.

Vortioxetine was statistically superior to placebo on the primary endpoint ( Digit Symbol Substitution Test or DSST ) ( p less than 0.05 ) and two key secondary endpoints, patient-reported Perceived Deficits Questionnaire ( PDQ ) and CGI-I.

Vortioxetine was statistically superior to placebo on the MADRS ( p less than 0.05 ) and UPSA ( p less than 0.001 ) change from baseline at week 8.

A pre-specified path-analysis to detect direct vs. indirect effects of treatment on cognition supported that the beneficial impact of Vortioxetine on cognitive performance is mostly a direct effect and not only due to alleviation of overall depressive symptoms.

Duloxetine was included in the study as an active reference to demonstrate assay sensitivity for depression. Duloxetine was not statistically significantly different from placebo on the primary study endpoint ( DSST ) or UPSA, but was significant on the PDQ, MADRS and CGI-I secondary endpoints.

Common adverse events ( more than 5% ) for Vortioxetine were nausea, headache, and diarrhea.

The findings from CONNECT study add to previously reported clinical data showing that Vortioxetine improves cognitive performance in elderly patients with major depression.
Cognitive dysfunction is well-documented in the different phases of major depression, and plays an important role in functional recovery from major depression. A general assumption is that cognitive dysfunction is restored as mood symptoms of depression improve. This is also supported by studies that have shown that daily life functioning, including work and family life often remain impaired even in remission.
Research suggests that different factors may explain why improvement in depression-related symptoms is not followed by improvement in daily life functioning. These associated factors include residual symptoms, comorbidity, misdiagnosis and long-lasting cognitive impairment.
Cognition is defined as the mental action or process of acquiring knowledge and understanding through thought, experience and the senses. It can be seen as comprised of several domains such as for example attention, memory, producing and understanding language, learning, reasoning, problem solving, and decision making.
Cognition is generally impacted in major depression, and focus is often on four of the domains, executive function, attention, speed of processing and memory.

Vortioxetine is an inhibitor of serotonin ( 5-HT ) reuptake and 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. ( Xagena )

Source: Lundbeck, 2014