Metabolic dysfunction and insulin resistance in depression: mechanisms, evidence, and therapeutic implications

Major depressive disorder (MDD) remains one of the most frequently diagnosed mental health disorders and a leading cause of disability worldwide. The discovery of new treatments for MDD is necessary given up to 30% of individuals with MDD are resistant to current antidepressant treatments. The significant physiological interplay between MDD and metabolic conditions is crucial to consider for future therapeutics given the current obesity epidemic and the increased prevalence of treatment-resistant depression in individuals with metabolic dysfunction. The aim of this review is to discuss the relationship between metabolic dysfunction and MDD, while highlighting the potential antidepressant effects of insulin. There are interconnected perpetuating cycles involving hypothalamic-pituitary-adrenal (HPA) axis dysfunction, inflammation, obesity, insulin resistance, and MDD. Evidence on the efficacy of agents that target insulin resistance for depression is mixed and mechanisms by which these agents may improve depressive symptoms have not been clearly elucidated in studies reporting benefit. While there is a clear need to continue research on treatments that address the burden imposed by treatment-resistant depression, current data on whether insulin-sensitivity-targeting therapies can fill this gap remain limited. Clinically, routine metabolic screening in MDD could guide precision treatments targeting insulin pathways, particularly in those with metabolic dysfunction. Future studies considering the role of insulin, especially in those with insulin resistance, may enable development of novel therapeutics.