Background. Major depressive disorder (MDD) is one of the most prevalent mental illnesses globally affecting more than 300 million people. Cognitive deficits are currently investigated as a possible factor of functional decline.
Objectives: 1) to assess influence of cognitions among other MDD symptoms on functional impairment; 2) to compare effects of eight weeks’ vortioxetine versus escitalopram treatments on cognitions and consequent influence on various domains of functioning.
Materials and methods. This was a randomized, open-labeled, active-comparator, parallel-group clinical trial. At baseline, 119 MDD (according to DSM-5, Montgomery-Asberg Depression Rating Scale (MADRS) ≥ 7) patients and 71 healthy controls completed neurocognitive tests (Rey Auditory Verbal Learning Test (RAVLT), Trail Making Test B, Digit Symbol Substitution Test (DSST) and Sheehan Disability Scale (SDS). After 8 weeks’ vortioxetine/escitalopram treatment, 56 patients had repeated clinical and neuropsychological evaluations. Multiple linear regression models were performed to explore a potential relationship between functioning and depressive symptoms and performance of cognitive tests. To determine the relative importance of each independent variable in the regression models and lessen the impact of multicollinearity, we performed a Johnson relative weights (RW) analysis. RW measures to what extent (expressed in percent) each variable contribute to regression equation in combination with other variables. RWs for all predictors sum up to 100%. Relative importance weights were computed using the Lorenzo-Seva and Ferrando (2011) SPSS code. Differences in and between treatment groups with respect to the baseline and week 8 in the study outcome parameters were analyzed using mixed model for repeated measurements (MMRM). Lastly, multiple linear regression analysis was performed to explore relationships between change in severities of functioning and change in individual depressive symptoms after antidepressant treatment. Significance was set at p<0.05.
Results.
MADRS symptoms and functioning at baseline. For functioning at work, significant predictors were fatigue and decreased concentration with RW of 16.1% and 15.5%, respectively. For social functioning, significant predictors were decreased concentration (RW=18%), inability to feel (RW=14%), and reported sadness (RW=12%). The severity of disruption in family functioning depended on “inability to feel” (RW=14%), reported sadness (RW=13%), and pessimistic thoughts (RW=7%). Total functioning was predicted by the scores of inability to feel (RW=13%), reported sadness (RW=13%), concentration problems (RW=12%), and pessimistic thoughts (RW=11%). Demographic predictors were not significant for functioning in those models.
Cognitive symptoms and functioning at baseline. Performance at work (SDS item “work”) was significantly predicted by scores of RAVLT total immediate recall (RW=25%), RAVLT delayed recognition (RW=19%), and DSST (RW=13%). As for social and family functioning, they were significantly influenced only by RAVLT total immediate recall score with RW of 26% and 19%, respectively. The overall functioning was depended on RAVLT total immediate recall (RW=26%) and RAVLT delayed recognition (19%).
Depression severity after treatment. Mean MADRS total scores decreased during the treatment period in both groups without significant difference. Analogous patterns were seen for changes in CGI-S and CGI-I scores with prominently higher differences for vortioxetine versus escitalopram. As for response / remission rates, 83% of patients in the vortioxetine group were responders compared with 75% of patients in the escitalopram group, and 62% of patients in the vortioxetine group were remitters compared with 48% of patients in the escitalopram group.
Cognitive performance after treatment. At week 8, improvements relative to baseline were seen in performance across all cognitive tests in both groups, with numerical differences favoring vortioxetine. Significant differences in favor of vortioxetine were in tests of verbal memory: RAVLT total immediate recall (6.4 points, p=0.01), RAVLT retroactive interference (1.6 points, p=0.007), and RAVLT delayed recall (1.1 points, p=0.03). From baseline to week 8, the number of DSST correct symbols increased (improved) by 12.3 and 7.6 points for vortioxetine and escitalopram, respectively, with a mean difference between the treatments of 7.7 points in favor of vortioxetine (p=0.07, MMRM).
Patient-rated functioning after treatment. Patients in both treatment groups improved in level of functioning as assessed by the SDS during the 8-week treatment period, with a significant between-treatment difference across all domains in favor for vortioxetine.
The influence of improvements of cognitive dysfunction on all aspects of functioning. According to obtained data, improvement of cognitive functioning (assessed by MADRS) played a significant role along with hypothymia on workplace performance improvement (β=0.35, p=0.03). Whereas, overall functioning recovery was predicted only by improvements in “concentration” item (β=0.44, p=0.008). Improvements of other MDD symptoms according to MADRS were not significant. As for the specific cognitive tests, there were significant associations between improvements in RAVLT immediate recall, RAVLT delayed recall recognition, and DSST test scores and working functioning. Total functioning change was significantly associated with change in RAVLT delayed recall recognition and DSST test scores.
Conclusions. Cognitive impairments predominantly affect social functioning and are among the crucial contributors in working and total functioning along with the core MDD symptoms – anhedonia and hypothymia in patients with MDD. Short-term (working) memory impairments are associated with all aspects of everyday functioning. Executive dysfunction makes additional contribution to workplace performance disturbances. At week eight, vortioxetine compared to escitalopram treatment greater improved the parameters of short-term (working) memory, executive disturbances, attention, and processing speed in MDD patients. Similarly, the effect of vortioxetine on working, social, family, and total functioning was significantly higher compared to that of escitalopram. Improving in cognitions is the most significant factor for total functioning recovery and among crucial contributors for workplace performance recovery. Vortioxetine was superior to escitalopram in response and remission rates.
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