Major depressive disorder (MDD) is associated with cognitive dysfunction encompassing several domains,
including memory, executive function, processing speed and attention. Cognitive deficits persist in a significant
proportion of patients even in remission, compromising psychosocial functioning and workforce performance. While
monoaminergic antidepressants may improve cognitive performance in MDD, most antidepressants have limited clinical
efficacy. The overarching aims of this review were: (1) to synthesize extant literature on putative biological pathways
related to cognitive dysfunction in MDD and (2) to review novel neurotherapeutic targets for cognitive enhancement in
MDD. We found that reciprocal and overlapping biological pathways may contribute to cognitive dysfunction in MDD,
including an hyperactive hypothalamic-pituitary-adrenal axis, an increase in oxidative and nitrosative stress, inflammation
(e.g., enhanced production of pro-inflammatory cytokines), mitochondrial dysfunction, increased apoptosis as well as a
diminished neurotrophic support. Several promising neurotherapeutic targets were identified such as minocycline, statins,
anti-inflammatory compounds, N-acetylcysteine, omega-3 poliunsaturated fatty acids, erythropoietin, thiazolidinediones,
glucagon-like peptide-1 analogues, S-adenosyl-l-methionine (SAMe), cocoa flavonols, creatine monohydrate and lithium.
Erythropoietin and SAMe had pro-cognitive effects in randomized controlled trials (RCT) involving MDD patients.
Despite having preclinical and/or preliminary evidences from trials suggesting possible efficacy as novel cognitive
enhancing agents for MDD, no RCT to date was performed for most of the other therapeutic targets reviewed herein. In
conclusion, multiple biological pathways are involved in cognitive dysfunction in MDD. RCTs testing genuinely novel
pro-cognitive compounds for MDD are warranted.