title: Cognitive dysfunction in depression - pathophysiology and novel targets.
abstract: 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.
authors.forename: Andre F
authors.initials: AF
authors.lastname: Carvalho
authors.forename: Kamilla K
authors.initials: KK
authors.lastname: Miskowiak
authors.forename: Thomas N
authors.initials: TN
authors.lastname: Hyphantis
authors.forename: Cristiano A
authors.initials: CA
authors.lastname: Kohler
authors.forename: Gilberto S
authors.initials: GS
authors.lastname: Alves
authors.forename: Beatrice
authors.initials: B
authors.lastname: Bortolato
authors.forename: Paulo Marcelo
authors.initials: PM
authors.lastname: G Sales
authors.forename: Rodrigo
authors.initials: R
authors.lastname: Machado-Vieira
authors.forename: Michael
authors.initials: M
authors.lastname: Berk
authors.affiliation: Department of Clinical Medicine, Faculty of Medicine, Federal University of Ceara, Rua Prof. Costa Mendes, 1608, 4o andar, 60430-040, Fortaleza, CE, Brazil. andrefc7@terra.com.br.
authors.forename: Roger S
authors.initials: RS
authors.lastname: McIntyre
mesh_terms: D003072:Cognition Disorders / Q000209:etiology* / Q000628:therapy*; D003863:Depression / Q000150:complications*; D006801:Humans; D018697:Nootropic Agents / Q000627:therapeutic use*
chemical_list: D018697:Nootropic Agents