Neuroinflammation and Mitochondrial Dysfunction Link Social Stress to Depression

Major depressive disorder is a debilitating mental illness and a leading cause of global disease burden. While many etiological factors have been identified, social stress is a highly prevalent causative factor for the onset of depression. Unfortunately, rates of depression continue to increase around the world, and the recent COVID-19 pandemic has further exacerbated this mental health crisis. Though several therapeutic strategies are available, nearly 50% of patients who receive treatment never reach remission. The exact mechanisms by which social stress exposure promotes the development of depression are unclear, making it challenging to develop novel and more effective therapeutics. However, accumulating evidence points to a role for stress-induced neuroinflammation, particularly in treatment-resistant patients. Moreover, recent evidence has expanded the concept of the pathogenesis of depression to mitochondrial dysfunction, suggesting that the combined effects of social stress on mitochondria and inflammation may synergize to facilitate stress-related depression. In this chapter, we review evidence for neuroinflammation and mitochondrial dysfunction in the pathogenesis of social stress-induced depression and discuss these in the context of novel therapeutic targets for the treatment of depression.