Role of metabolic dysfunction in treatment resistance of major depressive disorder

Major depressive disorder (MDD) and metabolic syndrome (MetS) are both widespread and cause enormous morbidity. The presence of one syndrome approximately doubles the risk of the other. Standard antidepressant treatments lead to remission in less than a third of the patients; a majority of patients experience treatment resistance at some point during their illness. Research focusing on clinical and biological markers has yet to provide evidence for the cause(s) of treatment resistance. MDD and MetS share endocrine and immune abnormalities that account for their overlap and suggest potential mechanisms for treatment resistance for a subgroup of patients with MDD. Cortisol resistance and positive energy balance work together to create inflammation. Chronic inflammation leads to insulin resistance. In the brain, inflammation and insulin resistance cause changes in metabolic control, decreases in serotonin synthesis, decreased hedonic drive and lower hippocampal neurogenesis, all of which are consistent with the neurobiology of MDD. We hypothesize that treatment-resistant MDD may result when MetS reinforces the pathophysiology of MDD, making it harder to reverse.