An advisory panel of the Food and Drug Administration on Feb. 3 supported vortioxetine for the treatment of cognitive dysfunction associated with major depressive disorder.
The 8-2 approval vote of the FDA’s Psychopharmacologic Drugs Advisory Committee sets the stage for Takeda Pharmaceuticals, which markets vortioxetine (Brintellix) in the United States, to seek a change in prescribing information for the antidepressant, which already is approved to treat major depressive disorder (MDD).
Though it’s long been known that MDD is associated with cognitive dysfunction for many patients, no drug has yet been approved specifically to improve cognitive function in those suffering from depression. Dr. Tiffany Farchione, acting deputy director of the division of psychiatry products at the FDA, observed that the psychiatric community is still working to define treatment goals and outcome measures for cognitive dysfunction in MDD. “This came to us before we were quite ready,” she said of Takeda’s application for the new labeling for vortioxetine.
The possible utility of vortioxetine for alleviating cognitive dysfunction in MDD came from an exploratory clinical trial, termed ELDERLY, whose predetermined endpoints included measures of cognitive function. Since ELDERLY found significant improvement in cognitive function for vortioxetine, compared with both placebo and duloxetine for patients with MDD, two further pivotal clinical trials were conducted to address the question of efficacy for cognitive function.
The FOCUS pivotal clinical trial enrolled 602 adult patients with MDD. The 8-week, double blind, randomized trial randomized patients 1:1:1 to vortioxetine 10 or 20 mg or placebo. At the end of the trial, both doses of vortioxetine resulted in better improvement than placebo on a composite score of cognitive dysfunction (mean treatment effects of 0.36 for 10 mg and 0.33 for 20 mg, both P less than .0001). Further statistical analysis showed this effect to be largely independent of improvement in depressive symptoms.
The CONNECT pivotal clinical trial added a direct comparator, duloxetine (Cymbalta), to the mix. It also enrolled 604 adults with MDD and lasted 8 weeks, and found that patients on vortioxetine got significantly better scores on the Digit Single Substitution Test (DSST) than did those on placebo (P less than .05). In addition, the results showed significant improvement, compared with patients on placebo, on two objective functional measures designed to assess functioning in the real world.
Vortioxetine is a selective serotonin reuptake inhibitor that also may have direct action on serotonin receptors. According to the prescribing information, “The contribution of these activities to vortioxetine ’s antidepressant effect has not been established.” Recommended doses are 10 mg or 20 mg once daily.
A complementary morning session of the advisory committee was devoted to assessing whether cognitive dysfunction in MDD is an appropriate drug target and, if so, how best to assess cognition in MDD. One area of vigorous discussion remaining unresolved at the end of the morning’s talks was whether a functional assessment, in addition to neuropsychological testing, should be a required coprimary endpoint. There were no voting items for the morning session.
Panel members also weighed whether the DSST was a single measure that could assess cognitive dysfunction in MDD. Takeda’s discussion of the DSST emphasized that it correlated well with other items in a more extensive neuropsychological test battery, and that improvement on the DSST also correlated with some objective measures of function. From a practical standpoint, it can be administered in the office in a matter of minutes.
Some committee members wrestled with using a single brief test as a proxy for the nuances of human cognition. However, Dr. Murray Stein, professor of psychiatry and family & preventive medicine at the University of California, San Diego, voiced a position shared by many panelists: “Given the circumstances where the company was trying to pick a single cognitive measure, this was a good choice.”
The FDA usually takes the advice of its advisory panels.
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