A randomized, double-blind, placebo-controlled study of vortioxetine on cognitive function in depressed adults

Abstract

The efficacy of vortioxetine 10 and 20 mg/d vs. placebo on cognitive function and depression in adults with recurrent moderate-to-severe major depressive disorder (MDD) was evaluated. Patients (18-65 yr, N = 602) were randomized (1:1:1) to vortioxetine 10 or 20 mg/d or placebo for 8 wk in a double-blind multi-national study. Cognitive function was assessed with objective neuropsychological tests of executive function, processing speed, attention and learning and memory, and a subjective cognitive measure. The primary outcome measure was change from baseline to week 8 in a composite z-score comprising the Digit Symbol Substitution Test (DSST) and Rey Auditory Verbal Learning Test (RAVLT) scores. Depressive symptoms were assessed using the Montgomery-Åsberg Depression Rating Scale (MADRS). In the pre-defined primary efficacy analysis, both doses of vortioxetine were significantly better than placebo, with mean treatment differences vs. placebo of 0.36 (vortioxetine 10 mg, p < 0.0001) and 0.33 (vortioxetine 20 mg, p < 0.0001) on the composite cognition score. Significant improvement vs. placebo was observed for vortioxetine on most of the secondary objectives and subjective patient-reported cognitive measures. The differences to placebo in the MADRS total score at week 8 were -4.7 (10 mg: p < 0.0001) and -6.7 (20 mg: p < 0.0001). Path and subgroup analyses indicate that the beneficial effect of vortioxetine on cognition is largely a direct treatment effect. No safety concern emerged with vortioxetine. Vortioxetine significantly improved objective and subjective measures of cognitive function in adults with recurrent MDD and these effects were largely independent of its effect on improving depressive symptoms.

Trial registration: ClinicalTrials.gov NCT01422213.

Figures

Fig. 1.

Standardized effect size (Cohen's d) for the neuropsychological tests (FAS, OC). DSST, Digit Symbol Substitution Test; FAS, full-analysis set; OC, observed cases; RAVLT, Rey Auditory Verbal Learning Test; TMT, Trail Making Test, Stroop; SRT, simple reaction time task; CRT, choice reaction time task. *p < 0.05, **p < 0.01, ***p < 0.001 vs. placebo. p-values for TMT, Stroop, SRT and CRT are not corrected for multiplicity.

Fig. 2.

Estimated Montgomery-Åsberg Depression Rating Scale (MADRS) total scores from baseline to week 8 (FAS, MMRM by visit) and LOCF, FAS, ANCOVA). The mean improvement from baseline to week 8 in the MADRS total score was −10.9 points (placebo), −15.6 points (vortioxetine 10 mg), and −17.6 points (vortioxetine 20 mg). ANCOVA, analysis of covariance; FAS, full-analysis set; LOCF, last observation carried forward; MMRM, mixed model for repeated measures. Patient numbers at each visit are shown below the x-axis for each treatment group. **p < 0.01; ***p < 0.001 vs. placebo. p-values are not corrected for multiplicity.