Background: Cognitive dysfunction is a core transdiagnostic domain of Major Depressive
Disorder (MDD) and is a principal determinant of functional recovery. However, it has been insufficiently
targeted within the current therapeutic framework for MDD.
Objective: To highlight these unmet cognitive needs in MDD.
Method: An article search was conducted using PubMed from inception to November 2016: Major
Depressive Disorder (and/or variant) was cross-referenced with the following terms: antidepressants,
augmentation, cognition, cognitive deficits, cognitive dysfunction, functional outcomes, mechanism of
action, and treatment. Articles informed by observational studies, clinical trials, and review articles
relevant to the discussion of cognition and cognitive impairment in MDD were included for review.
Additional terms and citations previously not identified in the initial search were obtained from a
manual review of article reference lists.
Results: Cognitive deficits in MDD are replicable, non-specific, and clinically significant. Abnormalities
in the domains of learning/memory, executive function, attention, concentration, and processing
speed are consistently reported. Only two antidepressants (i.e., duloxetine and vortioxetine) have established
procognitive effects utilizing rigorous methodology in MDD. Most antidepressants improve
cognitive function(s), but the extent to which they directly exert pro-cognitive effects is not yet understood.
Conclusion: Cognitive dysfunction in MDD is a principal determinant of patient-reported outcomes
(e.g., psychosocial function). Healthcare providers are encouraged to screen for cognitive dysfunction
in MDD and familiarize themselves with the efficacy profiles of antidepressants on disparate cognitive