Towards a “Metabolic” Subtype of Major Depressive Disorder: Shared Pathophysiological Mechanisms May Contribute to Cognitive Dysfunction

Major depressive disorder (MDD) is frequently associated with significant cognitive dysfunction. Furthermore, MDD is often co-morbid with obesity and metabolic disorders. The aim of this review is to evaluate the pathophysiological role obesity and co-morbid metabolic disorders may play in cognitive dysfunction associated with MDD. We conducted a PubMed search from December 1st 2013 to May 31st 2014 of all English language publications including the following keywords: cognition, working memory, attention, executive functioning, inflammation, insulin, brain-derived neurotrophic factor, neurotrophins, incretins, glucagon-like peptide-1, adipokines, diabetes, oxidative stress and glucocorticoids, cross- referenced with MDD and obesity, metabolic disorders, or metabolic syndrome. Clinical and epidemiological studies indicate that metabolic disturbances may contribute to cognitive dysfunction in MDD. There are several overlapping pathophysiological mechanisms linking obesity and metabolic abnormalities to MDD including disturbances in the hypothalamic pituitary adrenal axis, abnormalities in brain-derived neurotrophic factor signaling, adipose-derived hormones, insulin signalling, inflammatory cytokines, as well as oxidative and nitrosative stress pathways. Based on current research results, this article presents several putative mechanisms underlying the effects of obesity and metabolic abnormalities on cognitive dysfunction in MDD. Metabolic MDD may represent a depression subtype with unique patho-etiological mechanisms. The diverse shared pathophysiological mechanisms elucidated in this review may provide novel targets for the prevention and/or treatment of cognitive deficits in MDD.