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.

Advances in understanding mechanisms and therapeutic targets to treat comorbid depression and cardiovascular disease.

Chronic or repeated social stress exposure often precipitates the onset of depression and cardiovascular disease (CVD). Despite a clear clinical association between CVD and depression, the pathophysiology underlying these comorbid conditions is unclear. Chronic exposure to social stress can lead to immune system dysregulation, mitochondrial dysfunction, and vagal withdrawal. Further, regular physical exercise is well-known to exert cardioprotective effects, and accumulating evidence demonstrates the antidepressant effect of exercise. This review explores the contribution of inflammation, mitochondrial dysfunction, and vagal withdrawal to stress-induced depression and CVD. Evidence for therapeutic benefits of exercise, anti-inflammatory therapies, and vagus nerve stimulation are also reviewed. Benefits of targeted therapeutics of mitochondrial agents, anti-inflammatory therapies, and vagus nerve stimulation are discussed. Importantly, the ability of exercise to impact each of these factors is also reviewed. The current findings described here implicate a new direction for research, targeting the shared mechanisms underlying comorbid depression-CVD. This will guide the development of novel therapeutic strategies for the prevention and treatment of these stress-related pathologies, particularly within treatment-resistant populations.