Antidepressants and Their Effect on Cognition in Major Depressive Disorder​

George I. Papakostas, MD

From the Clinical Trials Network and Institute, Massachusetts General Hospital, Boston

Cognitive symptoms are often present in patients with MDD, as part of during depressive episodes and residual symptoms.1–3 Randomized, placebo-controlled clinical trials investigating the effects of antidepressants on cognitive functioning in general and executive functioning in particular have been scarce,4,5 and, until recently, focused exclusively on older adults despite the fact that such symptoms are prevalent across all age groups affected by the illness (AV 1). In addition, a growing body of literature suggests that cognitive dysfunction and, in particular, executive dysfunction in MDD are difficult to treat with traditional antidepressants.2,5 For instance, Culang-Reinlieb and colleagues6 compared the use of sertraline and nortriptyline for 12 weeks in 63 adults over the age of 45 years with MDD. The cognitive test battery comprised the MMSE, Purdue Pegboard, CPT, TMTA, Stroop Test, and BSRT. Aside from improved post-treatment scores compared with baseline scores on the BSRT, a test of memory and verbal learning, in the subjects taking sertraline (P=.001), no statistically significant improvement was found with any of the other cognitive tests in either the sertraline- or nortriptyline-treated groups during the trial. This finding is surprising, given that substantial symptomatic improvement of depressive symptoms over time is a profound challenge in clinical trials of MDD, particularly those with no placebo control group.7 In summary, cognition and executive dysfunction represent a difficult-to-treat symptom of depression as well as a functional outcome measure of major relevance, a unique distinction among DSM symptoms of MDD. Therefore, the purpose of this article is to review and summarize the literature examining the efficacy of antidepressants in treating cognitive symptoms of MDD compared with placebo.

AV 1. The Difference Between Cognitive and Executive Functioning (00:35)


In a 2007 study,8 Raskin and colleagues measured the effects of duloxetine on cognitive functioning in 311 elderly outpatients with MDD (aged 65–90 years) using 4 different scales: the RAVLT, the DSST, the TDCT, and the LNST. That 8-week study found duloxetine to be superior to placebo in improving composite cognitive test scores (P<.02), which was defined a priori as the primary outcome measure. This was the first instance of a placebo-controlled trial in MDD selecting cognitive functioning as a primary outcome measure. Geriatric Depression Scale scores showed duloxetine to also be significantly more efficacious than placebo for improving depression (P≤.001).8 However, when the cognitive scales were viewed individually instead of as a composite set, duloxetine was shown to be significantly superior to placebo in improving only verbal learning (P=.003) and delayed recall (P=.02), as reflected by the RAVLT, whereas in the other 3 cognitive tests, which measured executive functioning, no significant differences between duloxetine and placebo were found.


The effects of the SSRI citalopram on cognitive symptoms in elderly patients (aged ≥75 years, N=174) with MDD were studied in 2009 by Culang and colleagues.4 The DSST was used as an exploratory outcome measure in this 8-week study. No numerical or statistical difference in DSST scores between citalopram- and placebo-treated patients was found either at baseline or endpoint (AV 2).

AV 2. The Effects of Citalopram and Placebo on Digit Symbol Substitution Test (DSST) Scores Among Elderly Patients (aged ≥75 years, N=174) (00:35)

Data from Culang et al9

Vortioxetine versus Duloxetine and/or Placebo

Vortioxetine is a multimodal antidepressant with affinity for the serotonin transporter as well as several serotonin receptors. Katona and colleagues9 compared the effects of vortioxetine, duloxetine, and placebo for 8 weeks in 452 outpatients with MDD age ≥65 years. Cognitive function, assessed using the DSST and RAVLT, was an a priori secondary outcome measure. Both vortioxetine and duloxetine were significantly more effective than placebo at reducing patients’ scores on the HDRS (P<.01 for vortioxetine and P<.001 for duloxetine). Both drugs improved performance on the RAVLT measures of acquisition and delayed recall, but only vortioxetine was superior to placebo in improving DSST performance. Although cognition was not the primary outcome measure, this study was the first instance in the literature in which a randomized controlled trial showed an antidepressant to be significantly superior to placebo in improving an established measure of executive functioning such as the DSST. Path analysis confirmed that 83% of the effect of vortioxetine on DSST scores was a direct effect independent of improvement in depressive symptoms, while the direct effect of duloxetine on DSST scores was 26%.


Whereas studies of cognitive function in MDD described above exclusively evaluated elderly patients, McIntyre and colleagues10 reported the first placebo-controlled trial to examine patients between the ages of 18 and 65 years. A composite cognitive functioning score employing the DSST and RAVLT was used as the primary measure for that study. In that 8-week study, 602 patients were randomly assigned to groups receiving placebo, a 10-mg/d dose of vortioxetine, or a 20-mg/d dose of vortioxetine. Results revealed that both doses were significantly superior to placebo in improving depressive symptoms (P<.001 for both doses), as well as overall cognitive functioning (P<.001 for both doses). Both doses produced significantly greater effect sizes versus placebo on the DSST (P<.001 for both) and the delayed recall portion of the RAVLT (P<.01 for both), and the 10-mg dose produced a significantly improved effect size versus placebo on the RAVLT acquisition test (P<.05). Patients’ cognitive functioning was also measured with a number of other validated scales, including the TMT, Stroop Test, SRT test, and CRT test (AV 3). Patients also reported improved cognitive functioning via the self-rated PDQ (P<.001 for both doses).

AV 3. Different Dosages of Vortioxetine in Patients with MDD (00:35)

Based on McIntyre et al10

Most recently, an 8-week study11 evaluated 10–20 mg/d of vortioxetine versus 60 mg/d of duloxetine and placebo in 602 outpatients with MDD aged 18-65 years; executive functioning was the primary outcome measure, assessed using the DSST. Vortioxetine was significantly more effective than placebo at improving DSST scores over the course of treatment (P<.05), but duloxetine was not. Replicating the results of the 2012 study by Katona and colleagues,9 path analysis confirmed that the cognitive benefit of vortioxetine was mainly a direct effect and largely independent of improvement in depressive symptoms.


Although cognition represents both a difficult-to-treat symptom of MDD as well as a relevant functional outcome measure, the efficacy of popular antidepressants compared with placebo in treating cognitive dysfunction in MDD has not been examined for most FDA-approved antidepressants. In addition, the vast majority of existing studies focus on elderly patients as opposed to those from age groups which constitute the majority of the workforce in developed as well as developing countries, despite the fact that studies have shown that cognitive dysfunction is common across all age groups affected by MDD. Of agents tested thus far in placebo-controlled trials (citalopram, duloxetine, vortioxetine), only the latter of the 3 has been studied in patients aged 18–65 years, and only the latter has been shown to be superior to placebo in improving measures of executive functioning and to do so across adult age groups. Both duloxetine and vortioxetine appear to result in greater improvements than placebo in immediate and delayed memory.

Given that cognitive impairment is a common residual symptom of depression, is a predictor of poor antidepressant treatment outcomes, and is linked to poor restoration of psychosocial functioning, cognitive functioning should be routinely assessed and considered when selecting the optimal treatment regimen for patients with MDD.

Clinical Points

  • Consider cognitive symptoms when selecting a medication for treating a patient with MDD because cognitive functioning is a predictor of treatment outcomes
  • Use cognitive scales at baseline and during treatment to evaluate patient symptoms and needs
  • Understand the effects of various antidepressant medications on cognition


BSRT = Buschke Selective Reminding Test; CPT = Continuous Performance Test; CRT = Choice Reaction Time; DSST = Digit Symbol Substitution Test; HDRS = Hamilton Depression Rating Scale; LNST = Letter-Number Sequencing Test; MADRS = Montgomery-Åsberg Depression Rating Scale; MDD = major depressive disorder; MMSE = Mini-Mental State Exam; PDQ = Perceived Deficits Questionnaire; RAVLT = Rey Auditory Verbal Learning Test; SNRI = serotonin-norepinephrine reuptake inhibitor; SRI = serotonin reuptake inhibitor; SRT = Simple Reaction Time; SSRI = selective serotonin reuptake inhibitor; TDCT = Two-Digit Cancellation Test; TMT = Trail-Making Test

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  1. Conradi HJ, Ormel J, de Jonge P. Presence of individual (residual) symptoms during depressive episodes and periods of remission: a 3-year prospective study. Psychol Med. 2011;41(6):1165–1174. PubMed
  2. Fava M, Graves LM, Benazzi F, et al. A cross-sectional study of the prevalence of cognitive and physical symptoms during long-term antidepressant treatment. J Clin Psychiatry. 2006;67(11):1754–1758. Full Text
  3. Papakostas GI. Cognitive symptoms in patients with major depressive disorder and their implications for clinical practice. J Clin Psychiatry. 2014;75(1):8–14. Abstract
  4. Culang ME, Sneed JR, Keilp JG, et al. Change in cognitive functioning following acute antidepressant treatment in late-life depression. Am J Geriatr Psychiatry. October,2009;17(10):881–888. PubMed
  5. Keefe RSE, McClintock SM, Roth RM, et al. Cognitive effects of pharmacotherapy for major depressive disorder: a systematic review. J Clin Psychiatry. 2014;75(8):864–876. Full Text
  6. Culang-Reinleib ME, Sneed JR, Keilp JG, et al. Change in cognitive functioning in depressed older adults following treatment with sertraline or nortriptyline. Int J Geriatr Psychiatry. August,2012;27(8):777–784. PubMed
  7. Papkostas GI, Østergaard SD, Iovieno N. The Nature of Placebo Response in Clinical Studies of Major Depressive Disorder. J Clin Psychiatry. 2015;76(4):456–466. Full Text
  8. Raskin J, Wiltse CG, Sheikh J, et al. Efficacy of duloxetine on cognition, depression, and pain in elderly patients with major depressive disorder: an 8-week, double-blind, placebo-controlled trial. Am J Psychiatry. 2007;164(6):900–909. PubMed
  9. Katona C, Hansen T, Olsen CK. A randomized, double-blind, placebo-controlled, duloxetine-referenced, fixed-dose study comparing the efficacy and safety of Lu AA21004 in elderly patients with major depressive disorder. Int Clin Psychopharmacol. 2012;27(4):215–223. PubMed
  10. McIntyre RS, Lophaven S, Olsen CK. A randomized, double-blind, placebo-controlled study of vortioxetine on cognitive function in depressed adults. Int J Neuropsychopharmacol. 2014;17(10):1557–1567. PubMed
  11. Mahableshwarkar A, Zajecka J, Jacobson W, et al. Efficacy of vortioxetine on cognitive function in adult patients with major depressive disorder: results of a randomized, double-blind, active-referenced, placebo-controlled trial. In: 29th CINP World Congress of Neuropsychopharmacology; June 24, 2014; Vancouver, British Columbia, Canada.