Carvalho, Andre F3; Miskowiak, Kamilla Woznica4; Hyphantis, Thomas N3; Kohler, Cristiano A3; Alves, Gilberto S3; Bortolato, Beatrice3; G Sales, Paulo Marcelo3; Machado-Vieira, Rodrigo3; Berk, Michael3; McIntyre, Roger S3
1 Psykiatrisk Center København afd O - Østerbro og Indre By, Psykiatrisk Center København, Mental Health Services, The Capital Region of Denmark2 Psykiatrisk Center København, Mental Health Services, The Capital Region of Denmark3 unknown4 Psykiatrisk Center København afd O - Rigshospitalet, Psykiatrisk Center København, Mental Health Services, The Capital Region of Denmark
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.
C N S and Neurological Disorders - Drug Targets, 2014, Vol 13, Issue 10, p. 1819-35