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Table 1 Potential therapeutic targets for the treatment of cognitive dysfunction in major depressive disorder (MDD)

From: Cognitive remission: a novel objective for the treatment of major depression?

Agent Putative mechanisms of action Clinical evidence [Ref. No.]
Vortioxetine 5-HT3/5HT7 receptor antagonist; partial agonist at the 5-HT1B receptor; agonist at 5-HT1A receptor; inhibitor of the 5-HT transporter Two multicenter RCTs having cognitive performance as the primary outcome measure were conducted in participants with MDD [91, 92]. Overall, vortioxetine displayed a significant procognitive effect over several domains, which was largely independent of the amelioration of affective symptoms. However, a recent meta-analysis found that the overall effect size was small (0.34) [20].
Lisdexamfetamine dimesylate D-amphetamine prodrug; enhances the efflux of dopamine and norepinephrine in the CNS A RCT found LDX augmentation to be efficacious in reducing self-reported executive dysfunction among participants with MDD (N = 143) with residual depressive symptoms [94].
Erythropoietin Readily crosses the BBB and increases the production of BDNF EPO improved verbal learning and memory in a preliminary RCT involving participants with treatment-resistant MDD (N = 40) [97]. This effect was largely mood-independent. However, cognitive performance was not the primary outcome measure in this trial.
Minocycline Promotes hippocampal neurogenesis; Anti-apoptotic effects; Anti-inflammatory activity; Antioxidant; Modulates glutamatergic transmission; Stabilizes the microglia No clinical trial has investigated the potential procognitive effects of minocycline in samples with MDD.
Thiazolidinediones Antagonist of PPAR-gamma; increased the production of BDNF; has anti-inflammatory and antioxidant activities No published clinical trial has investigated the effects of thiazolidinediones upon cognition in samples with MDD.
S-adenosyl methionine Major methyl-donor; essential for the synthesis of several neurotransmitters; involved in the synthesis of glutathione A post-hoc analysis of a preliminary RCT involving 40 SSRI-resistant participants with MDD found SAMe to improve in self-rated recall and word-finding difficulties compared to placebo [127].
Omega-3 PUFAs Anti-inflammatory and antioxidant activities; Increases the production of BDNF; diminishes microglia-related neuro-inflammation No published clinical trials to date have investigated the effects of omega-3 PUFAs on cognitive performance in samples with MDD.
Modafinil Pleotropic agent that targets several neurotransmitter systems (e.g., 5-HT, GABA, glutamate, orexin, and histamine). A small open-label trial has found that modafinil augmentation improved executive function in a sample with MDD [147].
Galantamine Rapidly reversible acetylcholinesterase inhibitor and a potent modulator of the nicotinic receptor; affects monoamines, GABA and glutamate neurotransmitter systems. Two preliminary RCTs have found no evidence for a procognitive effect of galantamine augmentation in participants with MDD [150, 151].
Scopolamine Potent muscarinic antagonist; modulates 5-HT, neuropeptide Y, dopaminergic, and glutamatergic systems. A proof-of-concept RCT did not observe significant effects of scopolamine in a task measuring sustained attention in a sample with MDD [154].
N-acetylcysteine Pleotropic agent that modulates glutamate transmission; antioxidant; anti-inflammatory effect; anti-apoptotic activity; increases glutathione. No published trial has investigated the effects of NAC on cognitive function in samples with MDD.
Statins Increases BDNF; antioxidant; anti-inflammatory; inhibits the enzyme IDO; modulates the microglia. No published trial has investigated potential procognitive effects of statins in samples with MDD.