The Cognitive Effects of Antidepressants in Major Depressive Disorder: A Systematic Review and Meta-Analysis of Randomized Clinical Trials

Abstract

Background: Cognitive dysfunction is often present in major depressive disorder (MDD). Several clinical trials have noted a pro-cognitive effect of antidepressants in MDD. The objective of the current systematic review and meta-analysis was to assess the pooled efficacy of antidepressants on various domains of cognition in MDD.

Methods: Trials published prior to April 15, 2015, were identified through searching the Cochrane Central Register of Controlled Trials, PubMed, Embase, PsychINFO, Clinicaltrials.gov, and relevant review articles. Data from randomized clinical trials assessing the cognitive effects of antidepressants were pooled to determine standard mean differences (SMD) using a random-effects model.

Results: Nine placebo-controlled randomized trials (2 550 participants) evaluating the cognitive effects of vortioxetine (n = 728), duloxetine (n = 714), paroxetine (n = 23), citalopram (n = 84), phenelzine (n = 28), nortryptiline (n = 32), and sertraline (n = 49) were identified. Antidepressants had a positive effect on psychomotor speed (SMD 0.16; 95% confidence interval [CI] 0.05-0.27; I(2) = 46%) and delayed recall (SMD 0.24; 95% CI 0.15-0.34; I(2) = 0%). The effect on cognitive control and executive function did not reach statistical significance. Of note, after removal of vortioxetine from the analysis, statistical significance was lost for psychomotor speed. Eight head-to-head randomized trials comparing the effects of selective serotonin reuptake inhibitors (SSRIs; n = 371), selective serotonin and norepinephrine reuptake inhibitors (SNRIs; n = 25), tricyclic antidepressants (TCAs; n = 138), and norepinephrine and dopamine reuptake inhibitors (NDRIs; n = 46) were identified. No statistically significant difference in cognitive effects was found when pooling results from head-to-head trials of SSRIs, SNRIs, TCAs, and NDRIs. Significant limitations were the heterogeneity of results, limited number of studies, and small sample sizes.

Conclusions: Available evidence suggests that antidepressants have a significant positive effect on psychomotor speed and delayed recall.

Keywords: antidepressants; cognitive function; executive function; major depressive disorder; psychomotor speed; working memory.

Figure 1.

Preferred Reporting Items for Systematic Reviews and Meta-Analyses flow diagram of study selection.

Figure 2.

Pooled effect for placebo-controlled trials assessing psychomotor speed. CI, confidence interval; DSST, Digit Symbol Sign Test; SD, standard definition.

Figure 3.

Pooled effect of placebo-controlled trials assessing psychomotor speed sub-grouped based on age greater or less than 65 years. CI, confidence interval; DSST, Digit Symbol Sign Test; SD, standard definition.

Figure 4.

Funnel-plot of placebo-controlled trials assessing psychomotor speed. SE, standard error; SMD, standard mean differences.

Figure 5.

Pooled effect for placebo-controlled trials assessing cognitive control (Stroop test). CI, confidence interval; SD, standard definition.

Figure 6.

Pooled effect for placebo-controlled trials assessing executive function (Trails Making Test-B). CI, confidence interval; SD, standard definition.

Figure 7.

Pooled effect for placebo-controlled trials assessing delayed recall (Rey Auditory Verbal Learning Test). CI, confidence interval; SD, standard definition.

Figure 8.

Pooled effect on memory for selective serotonin reuptake inhibitors (SSRI)/selective serotonin and norepinephrine reuptake inhibitors (SNRI) versus tricyclic antidepressants (TCA). CI, confidence interval; RBMT, Rivermead Behavioural Memory Test; SD, standard definition; STM, short term memory.

Figure 9.

Pooled effect on working memory for selective serotonin reuptake inhibitors (SSRI) versus norepinephrine and dopamine reuptake inhibitors (NDRI). CI, confidence interval; SD, standard definition; SNRI, selective serotonin and norepinephrine reuptake inhibitors.

Figure 10.

Pooled effect on psychomotor speed (Digit Symbol Sign Test [DSST]) for sertraline versus fluoxetine. CI, confidence interval; SD, standard definition.