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.