A Network Meta-Analysis Comparing Effects of Various Antidepressant Classes on the Digit Symbol Substitution Test (DSST) as a Measure of Cognitive Dysfunction in Patients with Major Depressive Disorder

Abstract

Background: Major depressive disorder is a common condition that often includes cognitive dysfunction. A systematic literature review of studies and a network meta-analysis were carried out to assess the relative effect of antidepressants on cognitive dysfunction in major depressive disorder.

Methods: MEDLINE, Embase, Cochrane, CDSR, and PsychINFO databases; clinical trial registries; and relevant conference abstracts were searched for randomized controlled trials assessing the effects of antidepressants/placebo on cognition. A network meta-analysis comparing antidepressants was conducted using a random effects model.

Results: The database search retrieved 11337 citations, of which 72 randomized controlled trials from 103 publications met the inclusion criteria. The review identified 86 cognitive tests assessing the effect of antidepressants on cognitive functioning. However, the Digit Symbol Substitution Test, which targets multiple domains of cognition and is recognized as being sensitive to change, was the only test that was used across 12 of the included randomized controlled trials and that allowed the construction of a stable network suitable for the network meta-analysis. The interventions assessed included selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, and other non-selective serotonin reuptake inhibitors/serotonin-norepinephrine reuptake inhibitors. The network meta-analysis using the Digit Symbol Substitution Test showed that vortioxetine was the only antidepressant that improved cognitive dysfunction on the Digit Symbol Substitution Test vs placebo {standardized mean difference: 0.325 (95% CI = 0.120; 0.529, P=.009}. Compared with other antidepressants, vortioxetine was statistically more efficacious on the Digit Symbol Substitution Test vs escitalopram, nortriptyline, and the selective serotonin reuptake inhibitor and tricyclic antidepressant classes.

Conclusions: This study highlighted the large variability in measures used to assess cognitive functioning. The findings on the Digit Symbol Substitution Test indicate differential effects of various antidepressants on improving cognitive function in patients with major depressive disorder.

Keywords: cognitive dysfunction; major depressive disorder; network meta-analysis; systematic literature review; vortioxetine.

Figure 1.

Flow diagram for the identification and selection of studies. Note: 12 studies that assessed Digit Symbol Substitution Test (DSST) were included in the final network of evidence. Abbreviations: ADT, antidepressant therapy; MDD, major depressive disorder; RCT, randomized controlled trial.

Figure 2.

Network for the (a) by-class analysis and (b) by-treatment analysis. Note: The size (area) of the nodes is proportional to the number of patients on treatment. The width of the lines is proportional to the number of patients in trials with direct comparison between the nodes. The numbers on the lines indicate the number of trials with direct comparisons, if it is more than one. Abbreviations: MOAI, monoamine-oxidase inhibitor; SNRI, serotonin and norepinephrine reuptake inhibitor; SSRI, selective serotonin reuptake inhibitor; TCA, tricyclic antidepressant.

Figure 3.

Standardized mean differences in Digit Symbol Substitution Test (DSST) of antidepressants based on direct evidence from clinical studies included in the network of evidence. Abbreviations: SMD, standardized mean difference.

Figure 4.

Standardized mean difference vs placebo (a) by-class analysis and (b) by-treatment analysis. Abbreviations: CIT, citalopram; DES, desipramine; DUL, duloxetine; ESC, escitalopram; FLU, fluoxetine; MOAI, monoamine-oxidase inhibitor; NOR, nortriptyline; PHE, phenelzine; SER, sertraline; SNRI, serotonin and norepinephrine reuptake inhibitors; SSRI, selective serotonin reuptake inhibitors; TCA, tricyclic antidepressants; VOR, vortioxetine. *P<.05; ** P<.01.

Table 2.

Treatment Effect Estimates (standardized mean differences of DSST change from baseline)